WO2024240962A1

WO2024240962A1 - Gm-csf-encoding nucleic acids, pharmaceutical compositions, methods and uses thereof

Info

Publication number: WO2024240962A1
Application number: PCT/EP2024/064541
Authority: WO
Inventors: Carsten Rudolph; Steffen Meyer; Thomas LANGENICKEL; Manish ANEJA; Günther HASENPUSCH; Johannes Geiger; Alexandra SEMMLER
Original assignee: Ethris GmbH
Current assignee: Ethris GmbH
Priority date: 2023-05-25
Filing date: 2024-05-27
Publication date: 2024-11-28
Anticipated expiration: 2025-11-25

Abstract

Described are nucleic acids encoding GM-CSF and other proteins related to interstitial lung disease (ILD), pharmaceutical compositions, methods and uses thereof in methods of treating or preventing a GM-CSF deficiency and/or deficiency of other proteins targeted by autoantibodies, such as in autoimmune pulmonary alveolar proteinosis (PAP) and/or ILD.

Description

New PCT Application Ethris GmbH Vossius Ref.: AD3818 PCT S3 GM-CSF-encoding nucleic acids, pharmaceutical compositions, methods and uses thereof TECHNICAL FIELD The present invention relates generally to the field of immunology and pneumology. More particularly, it concerns to nucleic acids encoding GM-CSF, pharmaceutical compositions comprising said nucleic acids, and their use in methods of treatment or prevention of a disease related to a GM-CSF deficiency. BACKGROUND OF THE INVENTION Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional cytokine that regulates inflammatory responses, including emergency responses in the bone marrow. GM-CSF has been implicated in several diseases, including acute myeloid leukemia, multiple myeloma, chronic granulomatous disease, myelodysplastic syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, pulmonary fibrosis, sepsis, chronic obstructive pulmonary disease and pulmonary alveolar proteinosis. Mice deficient in GM-CSF develop normally, apart from displaying a lung phenotype similar to pulmonary alveolar proteinosis (PAP) in humans. PAP is a diffuse lung disease that results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homeostasis. PAP results in progressive dyspnea of insidious onset, hypoxaemic respiratory failure, secondary infections, and pulmonary fibrosis. GM-CSF has been identified as an indispensable mediator of macrophage maturation and surfactant catabolism. This led to the current understanding of the pathogenesis of most forms of PAP. In particular, GM-CSF mediates macrophage maturation by binding to its receptors, thereby facilitating degradation of surfactant. PAP can be classified into different types on the basis of the pathogenetic mechanism: Primary PAP is characterized by the disruption of GM-CSF signaling. Primary PAP can be further classified as autoimmune PAP (aPAP) (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits). In the case of autoimmune PAP autoantibodies against GM-CSF bind to GM-CSF and this prevents activation of alveolar macrophages (AM) in the lungs thereby leading to dysfunctional “foamy” AM. Secondary PAP results from various underlying conditions (see, e.g., Kumar et al., The Lancet 6 (2018), 554-565). Congenital PAP comprises surfactant production disorders (also known as pulmonary surfactant metabolic dysfunction disorders), a group of diseases caused by mutations in genes encoding surfactant proteins or proteins involved in surfactant production or lung development. The first use of GM-CSF as therapy of PAP was in 1996, in a single patient who received GM- CSF by subcutaneous administration, with marked improvement in symptoms and arterial oxygenation (Seymour et al., N. Engl. J. Med. 335 (1996), 1924-1925). Follow-up studies in patients with autoimmune PAP receiving subcutaneous GM-CSF in escalating doses for 3 or 6- 12 months resulted in overall response rates of 43% and 48%, respectively (Seymour et al., Am. J. Respir. Crit. Care Med 163 (2001), 524-531; Venkateshiah et al., Chest 130 (2006), 227-237). The administration of aerosolized recombinant GM-CSF in autoimmune PAP demonstrated better results (76.5% versus 48.4%) if compared with the subcutaneous route (Piloni and Campo, Expert Opin. Orphan Drugs 7(2019), 117-123). During inhalation GM-CSF therapy, the local deposition of the drug within the alveoli permits a direct activity against neutralizing autoantibodies. However, the data supporting GM-CSF supplementation as first-line treatment for PAP are not conclusive (Salvaterra and Campo, "Pulmonary alveolar proteinosis: from classification to therapy." Breathe 16.2 (2020). The finding that GM-CSF autoantibodies are the causative agent for autoimmune PAP led furthermore to the use of therapeutic approaches affecting their production and/or serum levels. Plasmapheresis to remove the autoantibodies and B-lymphocyte depletion using rituximab (an anti-B-cell monoclonal antibody) have been attempted (Malur and Kavuru, Respir. Res.13 (2012), 46; Kavuru et al., Am. J. Respir. Crit. Care Med.167 (2003), 1036). However, so far, the effectiveness of such approaches has not yet been proven. Rather to the contrary: in the PAGE trial by the Clinical and Translational Research Center (CTRC) at the Niigata University Medical and Dental Hospital, 64 patients received a twice daily inhaled administration of 125 µg Sargramostim (rhGM-CSF produced in yeast) over 24 weeks. The obtained results demonstrated a statistically significant, but clinically not relevant improvement of arterial oxygen gradient and a trend in benefit in 6-minute walk test. Moreover, an increase in GM-CSF neutralizing antibodies was reported and may have been driven by autoantibodies against the exogenous, inhaled GM- CSF (Tazawa et al., N. Engl. J. Med.381 (2019), 923-932; Ohashi et al., European Respiratory Journal 39 (2012), 777-780). Thus, there is still a need for an effective prophylaxis and/or treatment of GM-CSF related diseases and GM-CSF deficiencies in particular. The present invention addresses this need by providing the embodiments as recited in the claims. SUMMARY OF THE INVENTION The present invention relates to nucleic acids encoding GM-CSF, vectors, pharmaceutical compositions, and uses thereof in a method for the treatment of a GM-CSF deficiency. The present invention further relates to a method of treatment of a GM-CSF deficiency and in particular to a method of treatment of (a)PAP. Generally, the present invention relates to the finding that a deficient GM-CSF bioavailability is the main pathophysiological defect in multiple GM-CSF deficiencies and/or related diseases, for example in autoimmune PAP, and that the use of recombinant GM-CSF as previously used in the field to treat such diseases does not suffice to overcome such deficient bioavailability. The nucleic acids of the invention surprisingly overcome the limitations of previous therapies based on recombinant GM-CSF. While not wanting to be bound by any theory, it is believed that the present invention achieves advantageous results by increasing bioavailability of GM-CSF to its receptors. It is believed that the autocrine and/or paracrine stimulation resulting from delivery of the nucleic acids of the invention to the target and surrounding cells allows to generate sufficiently high surface concentrations of GM-CSF in the immediate vicinity of GM-CSF receptors to result in their activation even in the presence of neutralizing effectors such as neutralizing antibodies or in the case where the receptors are mutated and thus require higher GM-CSF concentrations to become activated. Achieving sufficiently high surface concentrations of recombinant GM-CSF protein to activate its receptors may not be feasible, as demonstrated herein, simply because of the spatial distance such exogenously applied protein needs to overcome without being degraded or being inactivated otherwise. While not wanting to be bound by any theory, it is believed that the spatial distance from an administration site to target receptors on target cells in a target organ is substantial, whereas it is not, when target and neighboring cells in a target organ endogenously produce sufficiently high levels the GM-CSF protein to enable receptor activation. For example, within the present invention any agent administered by inhaled administration may need to overcome mucociliary clearance and/or pass the numerous bifurcations in the airways to reach target cells and/or target receptors in high enough concentrations to be effective. In particular, we demonstrate that the nucleic acids of the invention allow to generate sufficiently high levels of GM-CSF to result in receptor activation even in the presence of neutralizing effectors such as neutralizing antibodies. In a mouse model of PAP, we demonstrate that the nucleic acids of the invention allow achieving therapeutic benefit. Thus, it is conceived that in the case of diseases caused by a GM-CSF deficiency, the nucleic acids of the invention can overcome limitations of current treatment options. It is also conceived that autocrine and/or paracrine stimulation resulting from the expression of GM-CSF encoded by a nucleic acid of the invention instead of treatment with an exogenous recombinant GM-CSF protein facilitates an efficient binding of GM-CSF protein to its receptor, thereby avoiding exposure to cellular factors (such as self-antigen-reactive CD4+ effector memory T (TEM) cells) and/or humoral factors (such as autoantibodies) which cause autoimmune GM-CSF related diseases such as autoimmune PAP. Thus, in one aspect, the present invention relates to nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, as well as to methods and uses employing the same and/or compositions comprising the same and the like. In another aspect, the present invention relates to compositions for delivering said nucleic acid in a manner that target cells in a target organ produce sufficiently high enough concentrations of GM-CSF to allow GM-CSF receptor activation. In a particular aspect of the present invention relates to a nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. A further aspect of the invention relates to a vector comprising the nucleic acid described herein. A further aspect of the invention relates to a cell comprising a nucleic acid coding for GM-CSF or a functional fragment thereof according to the invention. A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid as defined herein. A further aspect of the invention relates to a nucleic acid according to the invention encoding GM- CSF or a functional fragment thereof for use as a medicament. A further aspect of the invention relates to a cell according to the invention for use as a medicament. A further aspect of the invention relates to a pharmaceutical composition according to the invention for use as a medicament. A further aspect of the invention relates to a modified cell comprising an exogenous mRNA coding for GM-CSF for use as a medicament. A further aspect of the invention relates to a modified nucleic acid according to the invention encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM- CSF deficiency in a subject or patient. A further aspect of the invention relates to a cell according to the invention for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient. A further aspect of the invention relates to a pharmaceutical composition according to the invention for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient. A further aspect of the invention relates to a modified nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. A further aspect of the invention relates to a pharmaceutical composition comprising a modified nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, or fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. A further aspect of the invention relates to a pharmaceutical composition comprising an mRNA encoding GM-CSF for use in a method for treatment or prevention of autoimmune pulmonary alveolar proteinosis (aPAP). A further aspect of the invention relates to a use of the nucleic acid, the expression vector or pharmaceutical composition according to the invention in a method of activation and/or expansion of a macrophage and/or a granulocyte. The use may also be in-vitro or ex-vivo. Accordingly, a further aspect of the invention relates to an in-vitro or ex-vivo use of the nucleic acid, the expression vector or the pharmaceutical composition according to the invention in a method of activation and/or expansion of a macrophage, a monocyte and/or a granulocyte. A further aspect of the invention relates to a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid according to the invention, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof; wherein the nucleic acid comprises one or more sequences encoding GM-CSF or a functional fragment thereof being delivered to and expressed in a target cell that comprises a GM- CSF receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling). A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non- tuberculous mycobacterial (NTM) infection, lung cancer, aspergillosis or fungal infections caused by Aspergillus sp., such fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. A further aspect of the invention relates to the use of the nucleic acid, the expression vector or pharmaceutical composition of the invention in a method of activation and/or expansion of a macrophage, a monocyte and/or granulocyte. A further aspect of the invention relates to a method for restoring the ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein or an active fragment thereof to a target cell comprising said GM-CSF receptor or to a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell and therefore allowing GM-CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. A further aspect of the invention relates to a chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency, optionally comprising restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be delivered into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said target cell and allowing the one or more GM-CSF ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more GM-CSF ligand protein and its GM-CSF receptor. In a related aspect, the invention relates to a chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method for restoring a ligand- receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell and/or for increasing expression of GM-CSF ligand protein in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be delivered into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said target cell and allowing the one or more GM-CSF ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more GM-CSF ligand protein and its GM-CSF receptor and/or wherein the expression of GM-CSF ligand protein in a target cell is increased (compared to a (predetermined) reference expression level and/or compared to the expression level prior to delivery of the chemically modified mRNA. The method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell and/or for increasing expression of GM-CSF ligand protein can optionally comprise treating a GM-CSF deficiency. Terms like “in an autocrine manner” or “in a paracrine manner” can mean that GM-CSF is autocrinally expressed or paracrinally expressed, respectively. A further aspect of the invention relates to a kit comprising a nucleic acid or a cell or a pharmaceutical composition of the present invention and a delivery device, preferably, wherein the delivery device is a nebulizer. A further aspect of the invention relates to a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising, obtaining a cell from a subject and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof, and administering the cell into a subject. A further aspect of the invention relates to an ex vivo or in vitro method for expressing a GM-CSF in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof. The concept of the present invention can be generalized to proteins that benefit from the effect that autocrine and/or paracrine stimulation resulting from the expression of a protein encoded by a nucleic acid of the invention instead of treatment with an exogenous recombinant protein facilitates an efficient binding of the thereby expressed protein to its receptor. This has the advantage that exposure to cellular factors (such as self-antigen-reactive CD4+ effector memory T (TEM) cells) and/or humoral factors (such as autoantibodies) which cause autoimmune related diseases, e.g. autoimmune PAP, is avoided. In other words, without wishing to be bound by theory, the herein provided mRNA-based target protein expression (the nucleic acid/mRNA comprising a sequence encoding the proteins) results in pathway activation through para- and/or autocrine effects, e.g. avoiding contact between nucleic acid/mRNA-encoded protein and autoantibodies present in the body. Thus, the herein provided invention is particularly useful in the therapy/treatment of diseases and disorders associated/linked with/ characterized by (the presence of) autoantibodies (autoimmune diseases), specifically interstitial lung disease (ILD), PAP and aPAP, particularly wherein the diseases and disorders, specifically interstitial lung disease (ILD), PAP and aPAP, are associated/linked with autoantibodies, such as anti-GM-CSF, anti-synthetase, anti-MDA5, Anti-Scl70, Anti-eIF2B, Anti-PM/Scl, Anti-Ku, Anti-Topo I, Anti-Th/To, Anti-U11/U12 RNP, Anti-U1RNP, Anti-RF and/or ACPA autoantibodies; see, for example, Kuwana et al., Ther Adv Musculoskel Dis (2021), 13, 1-17, incorporated herein by reference in its entirety. In particular, the contents of Table 1 and Table 2 from Kuwana et al. are incorporated herein by reference. Thus, in a preferred aspect, the nucleic acid(s) (preferably mRNA(s)) comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof as disclosed herein is/are to be used in the therapy/treatment of diseases and disorders associated/linked with/ characterized by (the presence of) the respective autoantibodies, specifically interstitial lung disease (ILD), PAP and aPAP, particularly wherein the diseases and disorders, specifically interstitial lung disease (ILD), PAP and aPAP are associated/linked with autoantibodies, such as anti-GM-CSF, anti-MDA5, anti-synthetase, anti-Scl70, Anti-eIF2B, anti-PM/Scl, anti-Ku, anti-Topo I, anti-Th/To, anti-U11/U12 RNP, anti-U1RNP, anti-RF, and/or ACPA autoantibodies, respectively. For example, the nucleic acid(s) (preferably mRNA(s)) comprising a sequence encoding a GM-CSF, is/are to be used in the therapy/treatment of diseases and disorders associated/linked with/ characterized by (the presence of) the respective autoantibodies, specifically interstitial lung disease (ILD), PAP and aPAP, particularly wherein the diseases and disorders, specifically interstitial lung disease (ILD), PAP and aPAP, are associated/linked with anti-GM-CSF and/or GM-CSF receptor autoantibodies, and so on. GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, ACPA and/or citrullinated protein deficiency and/or anti-GM-CSF, anti-MDA5, anti- synthetase, anti-Scl70, Anti-eIF2B, anti-PM/Scl, anti-Ku, anti-Topo I, anti-Th/To, anti-U11/U12 RNP, anti-U1RNP, anti-RF, and/or ACPA autoantibodies is/are linked with interstitial lung disease (ILD). The deficiency may be caused by the presence of autoantibodies targeting said proteins. Thus, for example, the nucleic acid(s) (preferably mRNA(s)) comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein, is/are to be used in the therapy/treatment of diseases and disorders associated/linked with/characterized by (the presence of) the respective autoantibodies, specifically interstitial lung disease (ILD), PAP and aPAP, particularly wherein the diseases and disorders, specifically interstitial lung disease (ILD), PAP and aPAP, are associated/linked with anti-GM-CSF, anti-MDA5, anti-synthetase, anti-Scl70, Anti-eIF2B, anti-PM/Scl, anti-Ku, anti-Topo I, anti-Th/To, anti-U11/U12 RNP, anti-U1RNP, anti-RF, and/or ACPA autoantibodies. The mRNA coding for a citrullinated protein or a protein that in wild type form is citrullinated, might also be an mRNA modified to avoid citrullination partially or completely and maintaining a functional coded protein. For example, the mRNA sequence may be modified to code for amino acids other than arginine at positions where citrullination would typically occur. This can often be done by analyzing the protein sequence for consensus motifs commonly recognized by peptidylarginine deiminases (PAD enzymes), or by experimental data indicating which arginines are modified. In particular, the mRNA might be modified to substitute one or more arginines with lysine which has similar properties to arginine (positively charged) but cannot be citrullinated. Thus, in one aspect, the present invention relates to nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, as well as to methods and uses employing the same and/or compositions comprising the same and the like. The explanations and definitions provided herein for a nucleic acid encoding GM- CSF and/or GM-CSF protein apply, mutatis mutandis, to any of such other nucleic acids and/or proteins, including, but not limited to, nucleic acid encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein , or to the respective proteins. In another aspect, the present invention relates to compositions for delivering said nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein in a manner that target cells in a target organ produce sufficiently high enough concentrations of said protein to allow activation of the respective receptor. A particular aspect of the present invention relates to a nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. A further aspect of the invention relates to a vector comprising the nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof described herein. A further aspect of the invention relates to a cell comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof according to the invention. A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof as defined herein. A further aspect of the invention relates to a nucleic acid according to the invention encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use as a medicament. A further aspect of the invention relates to a cell comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use as a medicament. A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use as a medicament. A further aspect of the invention relates to a modified cell comprising an exogenous mRNA coding for GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use as a medicament. A further aspect of the invention relates to a modified nucleic acid according to the invention encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragment thereof for use in a method for the treatment or prevention of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency, a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein related disease or a disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency in a subject or patient. A further aspect of the invention relates to a cell comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use in a method for the treatment or prevention of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency, a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein related disease or a disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency in a subject or patient. A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use in a method for the treatment or prevention of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency, a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein related disease or a disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency in a subject or patient. A further aspect of the invention relates to a modified nucleic acid encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use in a method for treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non- tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. A further aspect of the invention relates to a pharmaceutical composition comprising a modified nucleic acid encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, or fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. A further aspect of the invention relates to a pharmaceutical composition comprising an mRNA encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein for use in a method for treatment or prevention of autoimmune pulmonary alveolar proteinosis (aPAP). A further aspect of the invention relates to a use of the nucleic acid, the expression vector or pharmaceutical composition according to the invention in a method of activation and/or expansion of a macrophage and/or a granulocyte. The use may also be in-vitro or ex-vivo. Accordingly, a further aspect of the invention relates to an in-vitro or ex-vivo use of the nucleic acid, the expression vector or the pharmaceutical composition according to the invention in a method of activation and/or expansion of a macrophage, a monocyte and/or a granulocyte. A further aspect of the invention relates to a method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof; wherein the nucleic acid comprising one or more sequences encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof is being delivered to and expressed in a target cell that comprises a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor, and/or citrullinated protein receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling). A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, aspergillosis or fungal infections caused by Aspergillus sp., such fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. A further aspect of the invention relates to the use of the nucleic acid, the expression vector or pharmaceutical composition of the invention in a method of activation and/or expansion of a macrophage, a monocyte and/or granulocyte. A further aspect of the invention relates to a method for restoring the ligand-receptor interaction between a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof to a target cell comprising said GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein receptor or to a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein to act in an autocrine manner, or alternatively expressing GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein in said neighboring cell and therefore allowing GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein to act in a paracrine manner, and optionally c) allowing the GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein to interact with its respective receptor and thereby restoring the interaction between the ligand GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein and its respective receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. A further aspect of the invention relates to a chemically modified mRNA encoding one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof for use in a method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency, optionally comprising restoring a ligand- receptor interaction between a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and its respective receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof is to be delivered into a target cell comprising said respective receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof is to be expressed in said target cell and allowing the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein ligand protein or any active fragments thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more ligand protein and its receptor. In a related aspect, the invention relates to a chemically modified mRNA encoding one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein ligand protein or any active fragments thereof for use in a method for restoring a ligand-receptor interaction between the ligand protein and its respective receptor in a target cell and/or for increasing expression of the ligand protein in a target cell, wherein: a) the chemically modified mRNA encoding one or more of the ligand protein or any active fragments thereof is to be delivered into a target cell comprising said receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of the ligand protein or any active fragments thereof is to be expressed in said target cell and allowing the one or more ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of the ligand protein or any active fragments thereof is to be expressed in said neighboring cell, and/or allowing the one or more ligand protein to act in a paracrine manner, and optionally c) the one or more ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more ligand protein and its receptor and/or wherein the expression of the ligand protein in a target cell is increased (compared to a (predetermined) reference expression level and/or compared to the expression level prior to delivery of the chemically modified mRNA. The method for restoring a ligand-receptor interaction between a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and its respective receptor in a target cell and/or for increasing expression of GM-CSF ligand protein can optionally comprise treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency. Terms like “in an autocrine manner” or “in a paracrine manner” can mean that GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein is autocrinally expressed or paracrinally expressed, respectively. A further aspect of the invention relates to a kit comprising a nucleic acid encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof, or a cell or a pharmaceutical composition comprising a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof and a delivery device, preferably, wherein the delivery device is a nebulizer. A further aspect of the invention relates to a method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiency in a subject in need thereof, the method comprising, obtaining a cell from a subject and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof, and administering the cell into a subject. A further aspect of the invention relates to an ex vivo or in vitro method for expressing a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragments thereof. In one aspect, the present invention relates to nucleic acid comprising a sequence encoding a GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein or any functional fragments thereof. In another aspect, the present invention relates to compositions for delivering said nucleic acid molecules in a manner that target cells in a target organ to produce sufficiently high enough concentrations of GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein to allow activation of their respective receptors. In another aspect, the present invention relates to compositions for delivering said nucleic acid in a manner that allows target cells in a target organ to produce sufficiently high enough concentrations of a GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein to allow activation of their respective receptors. In another aspect, the present invention relates to compositions for delivering said nucleic acid molecules in a manner that allows target cells in a target organ to produce sufficiently high enough concentrations of GM-CSF to allow GM-CSF receptor activation. A further aspect of the invention relates to a method for restoring the ligand-receptor interaction between a ligand protein being targeted by autoantibodies and its receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said ligand protein or an active fragment thereof to a target cell comprising said receptor or to a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing the expressed ligand protein to act in an autocrine manner, or alternatively expressing said ligand protein in said neighboring cell and therefore allowing the ligand protein to act in a paracrine manner, and optionally c) allowing the ligand protein to interact with its receptor and thereby restoring the interaction between the ligand protein and its receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. In some embodiments the method further comprises the treatment of a disease associated with treating a ligand or receptor protein deficiency. In preferred embodiments the disease is a lung disease, even more preferably a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. In some embodiments, the ligand protein is a GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein. A further aspect of the invention relates to a method of treating a ligand or receptor protein deficiency in a subject in need thereof, the method comprising, obtaining a cell from a subject and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding said ligand or receptor protein or a functional fragment thereof, and administering the cell into a subject. In some embodiments, the ligand protein is a GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein. In some embodiments, the receptor protein is a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein receptor. In some embodiments, the modified nucleic acid is a RNA encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or receptor protein. A further aspect of the invention relates to an ex vivo or in vitro method for expressing a ligand or receptor protein in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding said ligand or receptor protein or a functional fragment thereof. In some embodiments, the ligand protein is a GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein. In some embodiments, the receptor protein is a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein receptor. In some embodiments, the modified nucleic acid is a RNA encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or receptor protein. In some embodiments the ligand protein is a ligand protein selected from GM-CSF, MDA5, synthetase, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein. In preferred embodiments the ligand protein is a ligand protein related to a lung disease. In preferred embodiments the ligand protein is selected from GM-CSF, MDA5 (melanoma differentiation-associated protein 5), Scl70 (type I topoisomerase), and/or eIF2B (guanine nucleotide exchange factor for the eukaryotic initiation factor 2). In some embodiments the patient has autoantibodies against of the ligand proteins disclosed herein, preferably any of GM-CSF, MDA5, Scl70, and/or eIF2B. BRIEF DESCRIPTION OF DRAWINGS Figure 1 STAT5 western blot of AMJ2-C11 cells after treatment with 0.25/500 ng/mL recombinant GM-CSF. AMJ2-C11 cells were treated with 0.25 ng/mL or 500 ng/mL recombinant GM-CSF and sampled after 0.5 h, 1 h, 6 h, or 24 h. Subsequently cells were lysed for western blot. STAT5 signals were visible for cells sampled at all timepoints, for both doses. Also untreated cells exhibited strong STAT5 bands. Figure 2 shows a pSTAT5 western blot of AMJ2-C11 cells after treatment with 0.25/500 ng/mL recombinant GM-CSF. pSTAT5 signals could be observed upon treatment of AMJ2-C11 cells. Untreated cells did not exhibit any pSTAT5 signals. Slightly more intense bands 24 h after treatment thus correlate with more intense housekeeper signals and probably were not induced by prolonged treatment. No obvious dose-dependent pSTAT5 signal differences could be observed. Figure 3 STAT5 western blot of RAW264.7 cells after treatment with 0.01/100 ng/mL recombinant GM-CSF. RAW264.7 cells were treated with 0.01 ng/mL or 100 ng/mL recombinant GM-CSF and sampled after 0.5-, 1h, 6 h, or 24 h. Subsequently the cells were lysed for western blot. STAT5 signals were visible for cells sampled at all timepoints, for both doses. Also untreated cells exhibited STAT5 bands. Figure 4 pSTAT5 western blot of RAW264.7 cells after treatment with 0.01/100 ng/mL recombinant GM-CSF protein. pSTAT5 signals could be observed upon treatment of RAW264.7 cells. Untreated cells did not exhibit any pSTAT5 signals. Figure 5 PU.1 staining of western blots of murine macrophages after treatment with recombinant GM-CSF protein. RAW264.7 and AMJ2-C11 were treated with 0.25 ng/mL or 500 ng/mL recombinant GM-CSF and sampled after 0.5/1/6/24 h. Cells were lysed for PU.1 western blot. In none of the cell lines a GM-CSF-dependent increase in PU.1 signal could be observed. Increase in PU.1 signal after 24 h was also observed in untreated cells and was caused by continuous cell proliferation, also indicated by respective housekeeper bands which are much more intense after 24 h (blots on right). Figures 6a and 6b Target gene expression in RAW264.7 cells after treatment with recombinant GM-CSF protein. RAW264.7 cells were treated with 0.01/0.25/5/100/500 ng/mL recombinant GM-CSF and sampled 0.5/1/6/24 h after treatment. Subsequently cells were lysed for qPCR. No upregulation (fold change >2) of target genes (Abcg1, Fcgr1, Fcgr2b, Fcgr3, Clecl7a, PU.1) could be observed. Figures 7a-7c Target gene expression in AMJ2-C11 cells after treatment with recombinant GM-CSF protein. AMJ2-C11 cells were treated with 0.01/0.25/5/100/500 ng/mL recombinant GM-CSF and sampled 0.5/1/6/24 h after treatment. Subsequently cells were lysed for qPCR. No upregulation (fold change >2) of target genes (Abcg1, Fcgr1, Fcgr2b, Fcgr3, Clecl7a, PU.1) could be observed. Figures 8a-8b GM-CSF uptake of RAW264.7, and AMJ2-C11 cells after treatment with recombinant GM-CSF protein. Supernatants containing recombinant GM-CSF applied to cells was sampled after 0.5-24 h and analyzed via ELISA. Uptake was evaluated by comparing measured GM-CSF levels to the nominal concentrations (titled above graphs) that were applied to cells. Overall, in RAW264.7 and AMJ2-C11 cells a trend towards a reduction of GM-CSF in the supernatant over time could be observed. Figure 9 pSTAT5 western blot in RAW264.7 cells after treatment with recombinant GM- CSF. RAW264.7 cells were incubated with 0.25 ng/mL recombinant GM-CSF and +/- GM-CSF- neutralizing antibody for 0.5/1/6/24 h and subsequently lysed for western blot shown here. Untreated cells and cells incubated with neutralizing antibody do not exhibit any pSTAT5 signal at any timepoint. Cells incubated with recombinant GM-CSF for 0.5 h, but without antibody, exhibit a strong signal which decreases over time, after recombinant GM-CSF has been removed. Figure 10 Densitometry of pSTAT5 western blot of RAW264.7 after 0.5 h incubation with recombinant GM-CSF. RAW264.7 cells were incubated with 0.25 ng/mL recombinant GM-CSF and +/- GM-CSF-neutralizing antibody for 0.5/1/6/24 h and subsequently lysed for western blot. Cells incubated with recombinant GM-CSF for 0.5 h, but without antibody, exhibit a strong signal which decreases over time, after recombinant GM-CSF has been removed. Shown here is the densitometry of conducted western blot. Figures 11a and 11b Target gene expression in RAW264.7 cells after treatment with recombinant GM-CSF and monoclonal GM-CSF-neutralizing antibody. RAW264.7 cells were incubated with 0.25 ng/mL recombinant GM-CSF and +/- 3 µg/mL GM-CSF neutralizing antibody for 0.5 h. Subsequently, first cells were sampled. Others were placed in fresh medium without recombinant GM-CSF but again +/- antibody in order to investigate a comparatively short GM- CSF stimulus. After medium exchange, cells were sampled 1/6/24 h post initial start of treatment and subsequently lysed for qPCR. No upregulation (fold change >2) of target genes (Abcg1, Fcgr1, Fcgr2b, Fcgr3, PU.1) could be observed. (Fold changes were calculated by normalizing to untreated cells without antibody). Figure 12 Bar chart showing GM-CSF levels in supernatant of RAW264.7 after mRNA transfection measured by ELISA. Supernatant of RAW264.6 cells transfected with 47, 94, 188, 375 or 750 ng/well (94-1500 ng/cm²) GM-CSF mRNA were analyzed via ELISA. As early as 4 h after transfection, GM-CSF levels above the concentration of recombinant GM-CSF previously used in experiments with GM-CSF-neutralizing antibody, were obtained for all doses. In supernatants collected 0.5 h after transfection, no GM-CSF above the lower limit of quantification (LLOQ) could be detected. Shown here are the GM-CSF levels per dose per time point. Figure 13 Kinetics chart showing GM-CSF levels in supernatant of RAW264.7 after transfection measured by ELISA. Supernatants of RAW264.6 cells transfected with 47, 94, 188, 375 or 750 ng/well (94-1500 ng/cm²) GM-CSF mRNA were analyzed via ELISA. As early as 4 h after transfection, GM-CSF levels above the concentration of recombinant GM-CSF previously used in experiments with GM-CSF-neutralizing antibody, were obtained for all doses. In supernatants collected 0.5 h after transfection, no GM-CSF above the lower limit of quantification could be detected. Shown here is the same as in Figure 12, however depicted as kinetics, thus GM-CSF levels over time per dose. Figure 14 pSTAT5 western blot of RAW264.7 cells transfected with GM-CSF mRNA. The supernatants of RAW264.6 cells transfected with 47, 94, 188, 375 or 750 ng/well (94-1500 ng/cm²) GM-CSF mRNA were analyzed via ELISA. As early as 4 h after transfection, GM-CSF levels above the concentration of recombinant GM-CSF previously used in experiments with GM- CSF-neutralizing antibody, were obtained for all doses. In supernatants collected 0.5 h after transfection, no GM-CSF above the lower limit of quantification could be detected. Shown here is the same experiment as in Figure 13. Figure 15 pSTAT5 western blot of RAW264.7 cells with or without recombinant GM-CSF or modified mRNA and with or without mAb. Raw264.7 cells were incubated with or without GM- CSF neutralizing antibody (mAB) for 2 days prior to the experiment.24 h after seeding (again with or without mAb), cells were treated with recombinant GM-CSF [ng/mL] or transfected with GM- CSG mRNA [ng/cm²].1 h, 4 h, 6 h, and 24 h later, cells were sampled for western blot. Shown here are pSTAT5 bands. For lowest doses (6 ng/cm² mRNA and 5 ng/mL recombinant GM-CSF, respectively), pSTAT5 bands can be observed already 1 h after treatment with recombinant GM- CSF in presence of mAb, and already 4 h after transfection with GM-CSF mRNA in presence of mAb. Respective housekeeper bands are shown in Figure 16. Figure 16 GAPDH staining on western blot of RAW264.7 cells with or without recombinant GM-CSF or mRNA and with or without mAb. Raw264.7 cells were incubated with +/- GM-CSF neutralizing antibody (mAB) for 2 days prior to the experiment.24 h after seeding (again +/- mAb), cells were treated with recombinant GM-CSF [ng/mL] or transfected with GM-CSG mRNA [ng/cm²].1 h, 4 h, 6 h, and 24 h later, cells were sampled for western blot. Shown here are GAPDH bands (housekeeper). No difference in qualitative GAPDH expression between treatments and timepoints can be observed. Figure 17 qPCR results showing quantitative activation of GM-CSF downstream targets after transfection with modified mRNA normalized to Rplp0. RAW 264.7 cells were seeded in 96-well plates and transfected with GM-CSF mRNA or recombinant mGM-CSF (Lipofectamine MessengerMax; ratio 1:1.5). After 24 h cells were lysed and transcribed into cDNA. qPCR was performed using specific primers for each target gene. Figure 18 GM-CSF yield 1, 4, 6, and 24 h after transfection of GM-CSF mRNA in RAW264.7 cells. For all four timepoints (1, 4, 6, 24 h) clear dose-dependent GM-CSF yields were measured in RAW264.7 supernatant. Aspired yields of 100 and 1000 pg/mL are indicated with dotted lines. Figure 19 Neutralizing effect of monoclonal vs. polyclonal GM-CSF-neutralizing antibody. RAW264.7 cells were incubated 4 h with 1, 10, 100, or 1000 pg/mL recombinant GM-CSF in the presence or the absence of 5 µg/mL GM-CSF-neutralizing antibody. It is shown that polyclonal GM-CSF-neutralizing antibody (pAb) inhibits STAT5 phosphorylation more efficiently than monoclonal GM-CSF neutralizing antibody (mAb). 5 µg/mL antibody were used. Arrow 1: ≥10 pg/mL recombinant GM-CSF without antibody is sufficient to induce STAT5 phosphorylation. Arrow 2: pAb efficiently inhibits GM-CSF activation indicated as STAT5 phosphorylation even in presence of 1000 pg/mL recombinant GM-CSF. Arrow 3: mAb does not inhibit GM-CSF activity shown as STAT5 phosphorylation in the presence of 1000 pg/mL recombinant GM-CSF, but in the presence of 100 pg/mL. As a positive control, cells treated with 10,000 pg/mL recombinant GM-CSF were included on blot to indicate maximum pSTAT5 levels. This shows that a polyclonal antibody has a stronger inhibitory effect in GM-CSF signaling than a monoclonal, and also more closely represents the clinical situation in patients Figure 20 GM-CSF yield in RAW264.7 cells after transfection with GM-CSF mRNA in the absence of GM-CSF-neutralizing pAb. RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding cells were transfected with 0.3-300 ng/cm² GM- CSF mRNA. Supernatants were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted a total of three times (n=3).150 and 300 ng/cm² were only transfected once (n=1). GM-CSF ELISA was conducted in order to confirm predicted transfection yields. Shown here are yields after transfection in the absence of GM-CSF-neutralizing antibody. Figure 21 STAT5 phosphorylation in RAW264.7 cells after recombinant GM-CSF or GM-CSF modified mRNA in the presence or absence of polyclonal GM-CSF-neutralizing antibody. RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well. 24 h after seeding, cells were either transfected with 0.3-300 ng/cm² GM-CSF mRNA or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. Respective mRNA doses were chosen specifically in order to yield the same GM-CSF concentrations after 4 h as were applied with recombinant GM- CSF. Simultaneously with recombinant GM-CSF and transfection buffer, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing pAb. Cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted a total of three times (n=3). pSTAT5 western blots using cell lysates were conducted. pSTAT5 was semi-quantified via densitometry by normalization to GAPDH. Background level was defined as Mean_{(UT 4-24 h)}+2*SD_{(UT 4-24 h)}. Figure 22 Relative pSTAT5 abundance in relation to GM-CSF in supernatant after treatment of RAW264.7 cells with recombinant GM-CSF or GM-CSF mRNA and in the presence or absence of polyclonal GM-CSF-neutralizing antibody. RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding, sells were either transfected with 0.3-300 ng/cm² GM-CSF mRNA or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. Respective mRNA doses were chosen specifically in order to yield same GM-CSF concentrations after 4 h as were applied with recombinant GM-CSF. Simultaneous with recombinant. GM-CSF and transfection, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing pAb. Cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted a total of three times (n=3). pSTAT5 western blots using cell lysates were conducted. pSTAT5 was semi-quantified via densitometry by normalization to GAPDH. GM-CSF levels in supernatant after transfection with mRNA were quantified via ELISA. Shown here are pSTAT5 levels 4 h, 6 h, and 24 h after treatment in relation to GM-CSF levels in supernatant at respective time points. As mostly no GM- CSF could be quantified in supernatants of transfected cells treated with pAb, x-axis shows GM- CSF levels measured in supernatants of transfected cells in the absence of pAb. Concentrations of recombinant GM-CSF on x-axes are nominal concentrations used for treatments. Curves: nonlinear fit. Figure 23 STAT5 phosphorylation in RAW264.7 cells after treatment of RAW264.7 cells with recombinant GM-CSF or GM-CSF mRNA and with exchange of medium after 4 h but in constant presence of polyclonal GM-CSF-neutralizing antibody. RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding, cells were either transfected with 0.3- 30 ng/cm² GM-CSF mRNA or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. Respective mRNA doses were chosen specifically in order to yield same GM-CSF concentrations after 4 h as were applied with recombinant GM-CSF. Simultaneous with recombinant GM-CSF and transfection, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing pAb.4 h after treatment, medium was aspirated and replaced with fresh medium without recombinant GM-CSF or mRNA, but again supplemented with 5 µg/mL polyclonal GM-CSF-neutralizing antibody. Cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted twice (n=2). pSTAT5 western blots using cell lysates were conducted. pSTAT5 was semi-quantified via densitometry by normalization to GAPDH. Background level was defined as Mean(UT 4-24 h)+2*SD(UT 4-24 h). Figure 24 Relative pSTAT5 abundance in relation to GM-CSF in supernatant after treatment of RAW264.7 cells with recombinant GM-CSF or GM-CSF mRNA and with exchange of medium after 4 h but in constant presence of polyclonal GM-CSF-neutralizing antibody. RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding, cells were either transfected with 0.3-300 ng/cm² GM-CSF mRNA or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. Respective mRNA doses were chosen specifically in order to yield same GM-CSF concentrations after 4 h as were applied with recombinant GM-CSF. Simultaneous with recombinant GM-CSF and transfection, cells were also supplemented with 5 µg/mL GM-CSF- neutralizing pAb. 4 h after treatment, medium was aspirated and replaced with fresh medium without recombinant GM-CSF or mRNA, but again supplemented with 5 µg/mL polyclonal GM- CSF-neutralizing antibody. Cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted a total of two times (n=2). pSTAT5 western blots using cell lysates were conducted. pSTAT5 was semi-quantified via densitometry by normalization to GAPDH. GM- SCF levels in supernatant after transfection with mRNA were quantified via ELISA. Shown here are pSTAT5 levels 4 h, 6 h, and 24 h after treatment in relation to GM-CSF levels in supernatant at respective time points. As mostly no GM-CSF could be quantified in supernatants of transfected cells treated with pAb, x-axes show GM-CSF levels measured in supernatants of transfected cells without pAb. Concentrations of recombinant GM-CSF on x-axes are nominal concentrations used for treatments. Curves: nonlinear fit. Figure 25 mGM-CSF quantified in lung lysate, bronchoalveolar lavage fluid (BALF), and plasma of aged GM-CSF-/- mice, sacrificed 5-96 h after treatment. Aged GM-CSF-/- mice were treated with a single dose of GM-CSF mRNA ETH45 (ETH048T65, GM-CSF mRNA SEQ ID NO:12, modified with 100 % N1-Methylpseudouridine, formulated as LiNP with Formulation I) via nasal sniffing. Applied doses were 0, 0.3, 1, 3, and 10 µg. Timepoints of necropsy were 5, 24, 48, 72, and 96 h after application. Lungs, BALF, and plasma were collected and frozen until analysis. Lungs were lysed in 1X Triton X-100 + PI lysis buffer. Lung lysate, BALF (uncentrifuged), and plasma were analyzed using GM-CSF ELISA. Plasma samples were diluted 1:5. GM-CSF concentrations quantified in lung lysate were correlated to total lung weight. Figure 26 eGFP quantified in lung lysate, BALF, and plasma of aged GM-CSF-/- mice, sacrificed 24 h after treatment. Aged GM-CSF-/- mice were treated with a single dose mRNA encoding eGFP via nasal sniffing. Applied dose was 10 µg. Timepoint of necropsy was 24 h after application. Lungs, BALF, and plasma were collected and frozen until analysis. Lungs were lysed in 1X Triton X-100 + PI lysis buffer. Lung lysate, BALF (uncentrifuged), and plasma were analyzed using eGFP ELISA. All samples were analyzed undiluted. eGFP concentrations quantified in lung lysate were correlated to total lung weight. Figure 27 Lung weights of aged GM-CSF-/- mice, sacrificed 5-96 h after treatment. Aged GM-CSF-/- mice were treated with a single dose of mRNA ETH45 or mRNA encoding eGFP via nasal sniffing. Timepoints of necropsy were 5-96 h after application. Lungs were collected and frozen until analysis. Prior to lysis, lung weights were documented. Figure 28 Body weight of animals pre- (white dots) and post-dosing (black dots). Figure 29 Dose-dependent decrease in airway surface lining fluid (ASLF) turbidity. Optical density of uncentrifuged BALF at 600 nm was measured using plate reader. Data points were obtained from technical duplicates. OD was correlated to ASLF via urea-normalization. Figure 30 Total protein in ASLF. Total protein content in BALF was measured using bicinchoninic acid assay (BCA assay). Protein content was correlated to protein levels in ASLF via urea-normalization. Figure 31 Dose-dependent decrease of surfactant protein-D (SP-D) levels in ASLF. SP-D levels in BALF were measured with ELISA. SP-D concentrations were correlated to SP-D levels in ASLF via urea-normalization. Figure 32 SP-D levels in lung lysates. SP-D levels in lung lysate were measured with ELISA. All concentrations were above LLOQ. SP-D concentrations were correlated to concentration per lung weight. Figure 33 Cells counted in ASLF. Figure 34 Differential cell count of BALF by hematoxylin and eosin (HE) staining. BALF cell pellet was suspended in 500 µL BALF buffer (= PBS + 2 mM EDTA + 0.5 % BSA). Afterwards, 10 µL of BALF cell suspension was dropped on a new objective slide and let dried over night at RT. HE staining to characterize the cells was performed on the next day after drop preparation. In total 5 BALF drops slides per animal were counted and cells were morphologically characterized for: Macrophages, Lymphocytes, Granulocytes and ghost-like huge cells. 100 cells/slide were counted. Data represent mean % of 100 counted cells/slide. Figure 35 Quantification of Oil Red O positive macrophages – all treatment groups. Figure 36 Quantification of Oil Red O positive macrophages according to the same grading scheme. BALF cell pellet was resuspended in 500 µL BALF buffer (= PBS + 2 mM EDTA + 0.5 % BSA). Afterwards, 10 µL of BALF cell suspension was dropped on a new objective slide and let dried over night at RT. Half of the slides were stored at -20°C for later analysis, the other half was immediately stained by using the Polyscience Kit according to manufacturer instructions. In total 5 BALF drops/slides per animal were counted and positive macrophages were divided in “strong”, “medium” and “faint” positive macrophages.50 cells/slide were counted. Data represent mean % of 50 counted cells/slide. Figure 37 Exemplary bright field images of different types of Oil Red O positive macrophages. BALF cell pellet was resuspended in 500 µL BALF buffer (= PBS + 2 mM EDTA + 0.5 % BSA). Afterwards, 10 µL of BALF cell suspension was dropped on a new objective slide and let dried over night at RT. Oil Red O staining was performed by using the Polyscience Kit after drying. In total 5 BALF drops/slides per animal were counted and positive macrophages were divided in “strong”, “medium” and “faint” positive macrophages.50 cells/slide were counted. Data represent mean % of 50 counted cells/slide. Figure 38 GM-CSF levels in ASLF. GM-CSF levels in ASLF were measured with ELISA. Most concentrations were below LLOQ. GM-CSF concentrations were correlated to GM-CSF levels in ASLF via urea-normalization. Figure 39 GM-CSF levels in lung lysate. GM-CSF levels in lung lysate were measured with ELISA. All GM-CSF concentrations were below LLOQ. GM-CSF concentrations were correlated to GM-CSF concentration per lung weight. Figure 40 Percentual changes of body weight during the time course of the study. Figure 41 shows that there is no dose-dependent decrease in ASLF turbidity after centrifugation of BALF. Optical density of centrifuged BALF at 600 nm was measured using a plate reader. Data points were obtained from technical duplicates. OD was correlated to ASLF via urea-normalization. Figure 42 Bar chart showing relative pSTAT5 abundance (no medium-exchange). Differentiated THP-1 cells were treated with 10/100/1000 pg/mL recombinant hGM-CSF or transfected with 2/4/9 ng/cm² ETH45 (formulated as LiNP with Formulation I), both in combination with and without 5 µg/mL hGM-CSF-neutralizing pAb. No medium-exchange was conducted after initial treatment/transfection. Cells were collected 4 h, 6 h, or 24 h after treatment/transfection and lysed for pSTAT5 western blot. pSTAT5 was normalized to GAPDH to obtain relative pSTAT5 abundance. Background was calculated as MeanUT + 2* SDUT (UT: untransfected, SDUT: Standard deviation on the basis of untransfected treatment). Figure 43 Bar chart showing hGM-CSF levels in supernatant (no medium-exchange). Treatment as in Figure 42 above. Supernatant was collected 4 h, 6 h, or 24 h after treatment/transfection an analyzed with ELISA. hGM-CSF-neutralizing pAb was observed to interfere with hGM-CSF-detection in ELISA. Figure 44 Relative pSTAT5 abundance in relation to hGM-CSF in supernatant (no medium- exchange) showing that recombinant hGM-CSF induce dose-dependent STAT5 activation which declined over time, whereas STAT5 activation upon ETH45 was dose-independent and remained stable across all observed timepoints. In addition, whilst presence of hGM-CSF-neutralizing antibody completely abrogated STAT5 activation via recombinant hGM-CSF, STAT5 activation upon ETH45 remained unaffected. The figure shows relative pSTAT5 abundance, semi-quantified with western, blot was also correlated to hGM-CSF concentration in supernatant, quantified with ELISA. Due to ELISA’s lower limit of quantification of 20 pg/mL and interference of hGM-CSF- neutralizing antibody with ELISA, nominal concentrations of recombinant hGM-CSF were used for this correlation. For the same reason, hGM-CSF concentrations upon transfection of ETH45 in presence of neutralizing pAb are those quantified in supernatant of cells transfected with ETH45 without pAb. Figure 45 Relative pSTAT5 abundance (medium-exchange after 4 h) showing that ETH45 induces STAT5 activation to a similar extent upon all employed doses, independent of medium- exchange and independent of presence of hGM-CSF-neutralizing antibody. Differentiated THP-1 cells were treated with 10/100/1000 pg/mL recombinant hGM-CSF or transfected with 2/4/9 ng/cm² ETH45 (formulated as LiNP with Formulation I), both in combination with or without 5 µg/mL hGM-CSF-neutralizing pAb. At 4 h after treatment/transfection, medium-exchange was conducted. Cells were hereby also supplied with or without hGM-CSF-neutralizing pAb anew. Cells were collected 4 h, 6 h, or 24 h after treatment/transfection and lysed for pSTAT5 western blot. pSTAT5 was normalized to GAPDH in order to obtain relative pSTAT5 abundance. Background was calculated as MeanUT + 2* SDUT (UT: untransfected, SDUT: Standard deviation on the basis of untransfected treatment). Figure 46 hGM-CSF levels in supernatant (medium-exchange). Differentiated THP-1 cells were treated with 10/100/1000 pg/mL recombinant hGM-CSF or transfected with 2/4/9 ng/cm2 ETH45 (formulated as LiNP with Formulation I), both in combination with or without 5 µg/mL hGM- CSF-neutralizing pAb. Medium exchange was conducted 4 h after initial treatment/transfection. Cells were hereby also supplied with or without hGM-CSF-neutralizing pAb anew. Cells were collected 4 h, 6 h, or 24 h after treatment/transfection and lysed for pSTAT5 western blot. pSTAT5 was normalized to GAPDH to obtain relative pSTAT5 abundance. Background was calculated as MeanUT + 2* SDUT (UT: untransfected, SDUT: Standard deviation on the basis of untransfected treatment). Figure 47 Relative pSTAT5 abundance in relation to hGM-CSF in supernatant (medium- exchange after 4 h). Relative pSTAT5 abundance, semi-quantified with western blot was also correlated to hGM-CSF concentration in supernatant, quantified with ELISA. Due to ELISA‘s lower limit of quantification of 20 pg/mL and interference of hGM-CSF-neutralizing antibody with ELISA, nominal concentrations of recombinant hGM-CSF were used for this correlation. For the same reason, hGM-CSF concentrations upon transfection of ETH45 in presence of neutralizing pAb are those quantified in supernatant of cells transfected with ETH45 without pAb. Figures 48A to 48D Example 7, Experiment 1a western blots at 4 hours (A) 6 hours (B), 24 hours (C) and combined 4-6-24 hours (D). Figures 49A to 49D Example 7, Experiment 1b western blots at 4 hours (A) 6 hours (B), 24 hours (C) and combined 4-6-24 hours (D). Figures 50A to 50D: Example 7, Experiment 1c western blots at 4 hours (A) 6 hours (B), 24 hours (C) and combined 4-6-24 hours (D). Figures 51A to 51D Example 7, Experiment 2a western blots at 4 hours (A) 6 hours (B), 24 hours (C) and combined 4-6-24 hours (D). Figures 52A to 52D Example 7, Experiment 2b western at 4 hours (A) 6 hours (B), 24 hours (C) and, for comparison, 4, 6 and 24 hours in a single western blot (D). Figures 53A to 53D Example 7, Experiment 2c western blots at 4 hours (A) 6 hours (B), 24 hours (C) and, for comparison, 4, 6 and 24 hours in a single western blot (D). Figure 54: Western blot detecting pSTAT5 in RAW264.7 cell lysates after 1 hour of incubation with BALF or recombinant mGM-CSF. Western blot in RAW264.7 cells treated with BALF dilutions obtained from GM-CSF -/- mice treated with modified mRNA coding for GM-CSF or detecting pSTAT5 in RAW cells treated with recombinant GM-CSF. It is shown that 24 hours after treatment mice BALF contains expressed GM-CSF protein, capable of achieving maximum STAT5 phosphorylation ex-vivo, even after serial dilutions. Figure 55: Immune response to modified mRNA measured by IL-6 ELISA. DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the finding that a nucleic acid and in particular an mRNA which codes for GM-CSF allows for an efficient and dose dependent secretion of GM-CSF in transfected macrophages and an autocrine activation of GM-CSF target gene transcription. In particular it could be shown that the treatment of macrophages with a GM-CSF encoding mRNA results in activation of the pathway triggered by GM-CSF even in the presence of GM-CSF-neutralizing antibodies and does this much more effectively than recombinantly expressed GM-CSF proteins. This is particularly advantageous in treatments of GM-CSF deficiencies and GM-CSF related diseases. Moreover, herein it is shown that the nucleic acid displays a superior pharmacokinetic / pharmacodynamic profile in macrophages compared to recombinant GM-CSF. Experiments herein in GM-CSF -/- mice show that pulmonary delivery (nasal sniffing) of GM-CSF encoding mRNA results in dose-dependent GM-CSF titers, whereas physiological levels in wildtype mice were below the limit of detection. Moreover, it is shown that in GM-CSF -/- mice which had been treated with GM-CSF encoding nucleic acid via pulmonary delivery, the treatment was well tolerated and resulted in increased levels of GM-CSF in airway surface lining fluid (ASLF) as well as in relevant improvements of PAP phenotype. In the experiments with GM-CSF -/- mice it could also be shown that the treatment with GM-CSF encoding mRNA via pulmonary delivery leads to an activation of downstream signaling in macrophages as reflected by the presence of STAT5 or pSTAT5. Overall, it is shown that, surprisingly, a GM-CSF encoding nucleic acid is much more effective in treating GM-CSF deficiencies and GM-CSF related diseases, such as (autoimmune) PAP, than protein delivery and is, thus, a safe, effective and efficient treatment. Definitions For the sake of clarity and readability the following definitions are provided. Any technical feature mentioned in these definitions may be read on each and every embodiment of the invention. Additional definitions and explanations may be specifically provided in the context of these embodiments. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by the person skilled in the art. Comprising: The use of the term “comprising” as well as other grammatical forms such as “comprises” and “comprised” is not limiting. The terms “comprising”, “comprises” and “comprised” should be understood as referring to an open-ended description of an embodiment of the present invention that may, but does not have to, include additional technical features, in addition to the explicitly stated technical features. In the same sense, the term “involving” as well as other respective grammatical forms such as “involves” and “involved” is not limiting. The same applies for the term “including” and other grammatical forms such as “includes” and “included”. As used herein, the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise. Section headings throughout the description are for organizational purposes only. In particular, they are not intended as limiting for various embodiments described therein, and it is to be understood that embodiments (and features therein) described under one subheading may be freely combined with embodiments (and features therein) described under another subheading. Further, the terms “comprising”, “involving” and “including”, and any grammatical forms thereof, are not to be interpreted to exclusively refer to embodiments that include additional features to those explicitly recited. These terms equally refer to embodiments that consist of only those features that are explicitly mentioned. As used herein, the terms “comprising”/“including”/”involving” encompass the terms “consisting of” and “consisting essentially of”. Thus, whenever the terms “comprising”/“including”/” involving” are used herein, they can be replaced by “consisting essentially of” or, preferably, by “consisting of”. The terms “comprising”/“including”/”having” mean that any further component (or likewise features, steps and the like) can be present. The term “consisting of” means that no further component (or likewise features, steps and the like) can be present. The term “consisting essentially of” or grammatical variants thereof when used herein are to be taken as specifying the stated features, steps or components but do not preclude the addition of one or more additional features, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed product, composition, device or method and the like. Thus, the term “consisting essentially of” means that specific further components (or likewise features, steps and the like) can be present, namely those not materially affecting the essential characteristics of the product, composition, device or method. In other words, the term "consisting essentially of" (which can be interchangeably used herein with the term "comprising substantially"), allows the presence of other components in the product, composition, device or method in addition to the mandatory components (or likewise features, steps and the like), provided that the essential characteristics of the product, composition, device or method are not materially affected by the presence of other components. As used herein the term “about” refers to ± 10%, unless otherwise indicated. As used herein, “a” or “an” may mean one or more. GM-CSF: As used herein, the term GM-CSF refers to granulocyte-macrophage colony-stimulating factor, a glycoprotein that in mammals function as a cytokine, sometimes referred to as CSF2. Human wild type GM-CSF is as recited in GenBank accession number NM_000758.4. Murine wild type GM-CSF is as recited in GenBank accession number NM_009969.4. GM-CSF may be codon optimized. As used herein “GM-CSF ligand protein” refers to a GM-CSF protein itself, such as a GM-CSF protein that binds or is capable of binding to the GM-CSF receptor, for example, a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof. Functional fragment: As used herein, the term “functional fragment” refers to a protein fragment that still can achieve a function of a full-size protein or a function essentially corresponding to that of a full-size protein, for example in the case of GM-CSF a functional fragment may be able to bind and activate the GM-CSF receptor. “A functional fragment of a GM-CSF protein” can refer to a contiguous amino acid stretch of a GM-CSF protein as provided herein (e.g. as shown in SEQ ID NO:2) having substantially the same activity as the GM-CSF protein. “Substantially same” can mean ± 20 %, ± 10 %, ± 5 %, or ± 1 % activity compared to a reference activity, e.g. the activity of a GM-CSF protein as shown in SEQ ID NO:2. “A functional fragment of a GM-CSF protein” may be for example a truncated version of the full-length GM-CSF protein having substantially the same activity as the GM-CSF protein, e.g. has substantially the same activity/capacity of binding to the GM-CSF receptor as the GM-CSF protein. Nucleoside: As used herein “nucleoside” comprises a nucleobase and a five-carbon sugar. In the sense of the present invention a nucleobase is preferably one or more of adenine (A), cytosine (C), guanine (G), thymine (T) or uracil (U) and the five-carbon sugar is preferably a ribose or 2’- deoxyribose. The nucleobase, such as A, C, G, T or U can be one or more modified nucleobase. Nucleotide: As used herein “nucleotide” corresponds to a nucleoside further comprising one or more phosphate groups. Unmodified nucleotide/nucleoside: As used herein, the term “unmodified nucleotide” or “unmodified nucleoside” refers to a canonical A, C, G, T or U nucleotide or nucleoside, forming the fundamental units of the genetic code. Canonical nucleotide/nucleoside: As used herein, the term “canonical nucleotide” used herein refers to an unmodified A, C, G, T or U nucleotide or nucleoside. Modified nucleotide or nucleoside: The term “modified nucleotide” or “modified nucleoside” as used herein refers to any naturally occurring or non-naturally occurring isomers of A, C, G, T or U nucleotides/nucleosides as well as to any naturally occurring or naturally occurring analogs, alternative, modified nucleotide/nucleoside, or isomer thereof, having for example chemical modifications or substituted residues. Modified nucleotides can have a base modification and/or a sugar modification. Base modifications may be covalent modifications, of the base of a nucleotide of the nucleic acid, RNA or mRNA. Multiple base modifications are known to a skilled in the art. Modified nucleotides can also have phosphate group modifications, e.g., with respect to the 5’- cap of an mRNA molecule. In some embodiments, the modified nucleotide or nucleoside does not include modifications of the 5’- cap of an mRNA molecule. In some embodiments the modified nucleoside is a nucleoside only comprising modifications in the base. Modified nucleic acid, RNA or mRNA: As used herein, the term “modified” and the corresponding noun “modification” refers to a polynucleotide comprising modified nucleosides as defined herein. In particular, a nucleic acid sequence may be modified by replacing one or more canonical nucleotides/nucleosides/nucleobases in said sequence with modified nucleotides/nucleosides/nucleobases as described herein. For example, one or more canonical uridine in a nucleic acid can be replaced by one or more modified uridine, such as N1- methylpseudouridine or 5-Iodouridine (I₅U)/5-iodocytidine (I₅C). A corresponding modified nucleic acid may then comprise 100% N1-methylpseudouridine instead of uridine. In the sense of the present invention a modified nucleic acid is preferably a RNA and more preferably an mRNA. As used herein “nucleotides are modified” e.g. in the context of a polynucleotide generally means that a canonical nucleotide has been replaced or is replaced by a modified nucleotide of the same general type. For example, a polynucleotide comprising 100% modified uridines means that all canonical uridines are replaced with modified uridines. A nucleic acid of the present invention can be for example be modified by in vitro transcription (IVT), wherein the desired modified nucleoside or nucleotide is provided instead of the canonical one. When the nucleic acid of the present invention is produced using an in vitro polymerase synthesis process, the nucleic acid is preferably an mRNA and/or the polymerase is preferably a T7 polymerase. Modified cell: As used herein a “modified cell” is a cell that is contacted with a nucleic acid of the invention and comprises said synthetic nucleic acid and in particular an mRNA or modified RNA of the invention. Recombinant protein: As used herein, the term ’recombinant protein’ refers to proteins that have been produced in a heterologous system, that is, in an organism that naturally does not produce such a protein, or a variant of such a protein. Alternatively, the organism may naturally produce the protein, but in lower amounts so that the recombinant expression increases the amount of said protein. Typically, the heterologous systems used in the art to produce recombinant proteins are bacteria (e.g., Escherichia coli), yeast (e.g., Saccharomyces cerevisiae), insect cells or certain mammalian cell culture lines. Plasmid DNA (vectors): The term ’plasmid DNA’ or ’plasmid DNA vector’ refers to a circular nucleic acid (molecule), preferably to an artificial nucleic acid molecule. A plasmid DNA in the context of the present invention is suitable for incorporating or harboring a desired nucleic acid sequence, such as a nucleic acid sequence comprising a sequence encoding an RNA and/or an open reading frame encoding at least one peptide or polypeptide. Such plasmid DNA constructs/vectors may be storage vectors, expression vectors, cloning vectors, transfer vectors etc. A storage vector is a vector, which allows the convenient storage of a nucleic acid molecule, for example, of an RNA molecule. Thus, the plasmid DNA may comprise a sequence corresponding (coding for), e.g., to a desired RNA sequence or a part thereof, such as a sequence corresponding to the open reading frame and the 5’-and/or 3’UTR of an mRNA. An expression vector may be used for production of expression products such as RNA, e.g. mRNA in a process called RNA in vitro transcription. For example, an expression vector may comprise sequences needed for RNA in vitro transcription of a sequence stretch of the vector, such as a promoter sequence, e.g. an RNA promoter sequence, preferably T7, T3, SP6 or K11 RNA promoter sequences. In some embodiments the promoter comprises a sequence selected from SEQ ID NO:40 to SEQ ID NO:43. A cloning vector is typically a vector that contains a cloning site, which may be used to incorporate nucleic acid sequences (insert) into the vector. A cloning vector may be, e.g., a plasmid vector or a bacteriophage vector. A transfer vector may be a vector, which is suitable for transferring nucleic acid molecules into cells or organisms, for example, viral vectors. Preferably, a plasmid DNA vector in the sense of the present invention comprises a multiple cloning site, an RNA promoter sequence, optionally a selection marker, such as an antibiotic resistance factor, and a sequence suitable for multiplication of the vector, such as an origin of replication. Particularly preferred in the context of the present invention are plasmid DNA vectors, or expression vectors, comprising promoters for DNA-dependent RNA polymerases such as T7, T3, Sp6 and/or K11. Polynucleotide sequences: The skilled person is aware that, except where otherwise noted, polynucleotide sequences set forth in the present application will recite “T”s in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the “T”s would be substituted for “U”s. Thus, any of the RNA polynucleotides encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, where each “T” of the DNA sequence is substituted with “U” and vice versa. It is understood that when the disclosure refers to a DNA sequence (or DNA, polynucleotide DNA or similar terms as used herein), reference is made to corresponding exemplary DNA sequences provided herein, e.g. SEQ ID NO:45, SEQ ID NO:6, SEQ ID NO:63, SEQ ID NO:72, and/or SEQ ID NO:73, and vice versa. It is understood that when the disclosure refers to an RNA sequence (or RNA a polynucleotide RNA or similar terms as used herein), specifically an mRNA sequence (or mRNA a polynucleotide mRNA or similar terms as used herein) reference is made to corresponding exemplary RNA sequences provided herein, e.g. SEQ ID NO:1, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, and/or SEQ ID NO:39, and vice versa. Any of the nucleic acid sequences provided herein may also comprise codon optimized versions of themselves, e.g. codon optimized for expression in a desired (host) cell and/or subject. It is understood that terms like “nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof” also comprise (genetic) variants of the nucleic acids/(nucleotide) sequences encoding a GM-CSF protein or a functional fragment thereof provided herein (e.g. of the nucleic acids/(nucleotide) sequences shown in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73), as long as the nucleic acid substantially results in the GM-CSF protein or a functional fragment thereof, e.g. SEQ ID NO: 2, when being translated (this is meant by “encoding a GM-CSF protein or a functional fragment thereof”). Thus, the nucleic acids/nucleotide sequence encoding a GM-CSF protein or a functional fragment thereof (e.g. a protein shown in SEQ ID NO: 2) as provided herein, for example the nucleic acids/(nucleotide) sequences shown in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73), include (genetic) variants thereof encoding a GM-CSF protein or a functional fragment thereof, e.g. nucleic acids/(nucleotide) sequence having an identity of 94%, 95%, 96%, 97%, 98%, or 99% or more to e.g. SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, or SEQ ID NO:72, for example a nucleic acid/ nucleotide sequence which is degenerate as a result of the genetic code to the sequence shown in e.g. SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72 As used herein, the term "X% identity" or “identity of x%” is meant to describe the degree of sequence similarity between two nucleotide sequences by expressing the percentage of nucleotides in a first sequence that are identical to the corresponding nucleotides in a second sequence when aligned for maximum correspondence. It is determined by aligning the two sequences for optimal comparison, which may involve introducing gaps in either of the sequences to achieve the best alignment. The alignment can be performed using various sequence comparison algorithms or programs known in the art, such as BLASTn, CLUSTALW, or Smith- Waterman. The "% identity" value is calculated by taking the number of identical nucleotide positions divided by the total number of nucleotides in the shorter of the sequences (or the defined segment of comparison) and multiplying by 100. It serves as a quantitative representation of the similarity between two nucleotide sequences. For purposes of determining percentage identity of a first sequence relative to a second sequence, an analog (e.g., methylcytidine) matches cytidine, etc. In certain embodiments, the term "primary sequence" may be used to refer to a polynucleotide sequence without regard to whether or the level of modification, such that a primary sequence identical to CUCUCUA would include that sequence regardless of whether any or all of the recited nucleotides are modified (e.g., analogs of any one or more of C, U and A may be present and would be considered the same primary sequence). In certain embodiments, percent identity is only determined by reference to the portion of a given listed sequence corresponding to the coding sequence for, for example, GM-CSF. While in other embodiments, the percent identity is determined by reference to both the coding sequence and one or more non-coding sequences. In certain embodiments, the percent identity is determined across the entire length of a listed sequence (e.g., by reference to the entire length of a sequence provided herein). In certain embodiments, the percent identity of a polyribonucleotide is measured only with respect to the GM-CSF coding sequence-portion of SEQ ID NO: 1, and as DNA, SEQ ID NO: 45 (other non-coding sequences such as 5’ UTR, 3’UTR and poly A sequences are not considered when calculating percent identity, and the polyribonucleotide or DNA may or may not contain such regions). RNA: RNA is the usual abbreviation for ribonucleic acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotide monomers. These nucleotides are usually adenosine- monophosphate, uridine-monophosphate, guanosine-monophosphate and cytidine- monophosphate monomers, which are connected to each other along a so called backbone. The backbone is formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific order of the monomers, i.e. the order of the bases linked to the sugar/phosphate-backbone, is called the RNA-sequence. Usually RNA may be obtainable by transcription of a DNA-sequence, e.g., inside a cell. In eukaryotic cells, transcription is typically performed inside the nucleus or the mitochondria. In vivo, transcription of DNA usually results in the so-called premature RNA, which has to be processed into so-called messenger-RNA, usually abbreviated as mRNA. Processing of the premature RNA, e.g. in eukaryotic organisms, comprises a variety of different posttranscriptional-modifications such as splicing, 5’-capping, polyadenylation, export from the nucleus or the mitochondria and the like. The sum of these processes is also called maturation of RNA. The mature messenger RNA usually provides the nucleotide sequence that may be translated into an amino acid sequence of a particular peptide or protein. Typically, a mature mRNA comprises a 5’-cap, optionally a 5’UTR, an open reading frame, optionally a 3’UTR and a poly(A) sequence. Aside from messenger RNA, several non-coding types of RNA exist which may be involved in regulation of transcription and/or translation, and immunostimulation. The term "RNA" further encompasses other coding RNA molecules, such as viral RNA, retroviral RNA and replicon RNA, small interfering RNA (siRNA), antisense RNA, CRISPR RNA, ribozymes, aptamers, riboswitches, immunostimulating RNA, transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), microRNA (miRNA), and Piwi-interacting RNA (piRNA). mRNA: As used herein, the term messenger RNA (mRNA) refers to a single stranded messenger RNA nucleic acid encoding a protein which is capable of being translated when the mRNA is present within a cell. Typically, mRNA comprises a 5′-UTR, a protein coding region, and a 3′-UTR. mRNA may be generated by in vitro transcription from a DNA template. The in vitro transcription methodology is known to the skilled person. For example, there is a variety of in vitro transcription kits commercially available. Alternatively, mRNA can be produced in a cell by the endogenous transcription machinery, e.g. when an exogenous DNA template encoding said mRNA is provided to the cell. Poly(A) sequence: A poly(A) sequence, also called poly(A) tail or 3’-poly(A) tail, is typically understood to be a sequence of adenine nucleotides, e.g., of up to about 400 adenine nucleotides, e.g. from about 20 to about 400, preferably from about 50 to about 400, more preferably from about 50 to about 300, even more preferably from about 5, 5-10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 50 to about 250, most preferably from about 60 to about 250 adenine nucleotides. A poly(A) sequence is typically located at the 3’end of an mRNA. In the context of the present invention, a poly(A) sequence may be located within an mRNA or any other nucleic acid molecule, such as, e.g., in a vector, for example, in a vector serving as template for the generation of an RNA, preferably an mRNA, e.g., by transcription of the vector. The poly (A) may be a segmented poly (A) as described in WO 2020074642 A1, which is hereby incorporated by reference in its entirety. 5’-cap: A 5’-cap is an entity, typically a modified nucleotide entity, which generally "caps" the 5’- end of a mature mRNA. A 5’-cap may typically be formed by a modified nucleotide (cap analog), particularly by a derivative of a guanine nucleotide. Preferably, the 5’-cap is linked to the 5’- terminus via a 5’-5’-triphosphate linkage. A 5’-cap may be methylated, e.g. m7GpppN (e.g. m7G(5’)ppp(5’)G (m7G)), wherein N is the terminal 5’ nucleotide of the nucleic acid carrying the 5’- cap, typically the 5’-end of an RNA. Further examples of 5’cap structures include glyceryl, inverted deoxy abasic residue (moiety), 4’,5’ methylene nucleotide, 1 -(beta-D-erythrofuranosyl) nucleotide, 4’-thio nucleotide, carbocyclic nucleotide, 1 ,5-anhydrohexitol nucleotide, L- nucleotides, alpha-nucleotide, modified base nucleotide, threo-pentofuranosyl nucleotide, acyclic 3’,4’-seco nucleotide, acyclic 3,4-dihydroxybutyl nucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3 ’-3 ’-inverted nucleotide moiety, 3’-3’-inverted abasic moiety, 3 ’-2 ’-inverted nucleotide moiety, 3 ’-2 ’-inverted abasic moiety, 1 ,4-butanediol phosphate, 3’-phosphoramidate, hexylphosphate, aminohexyl phosphate, 3’-phosphate, 3’phosphorothioate, phosphorodithioate, or bridging or non-bridging methylphosphonate moiety. Further modified 5’-CAP structures which may be used in the context of the present invention are CAP1 (methylation of the ribose of the adjacent nucleotide of m7GpppN), CAP2 (methylation of the ribose of the 2nd nucleotide downstream of the m7GpppN), CAP3 (methylation of the ribose of the 3rd nucleotide downstream of the m7GpppN), CAP4 (methylation of the ribose of the 4th nucleotide downstream of the m7GpppN), ARCA (anti-reverse CAP analogue, modified ARCA (e.g. phosphothioate modified ARCA), inosine, N1-methyl-guanosine, 2’-fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. 5’-untranslated region (5’-UTR): As used herein, the term ’5’-UTR’ typically refers to a particular section of messenger RNA (mRNA). It is located 5’ of the open reading frame of the mRNA. Typically, the 5’-UTR starts with the transcriptional start site and ends one nucleotide before the start codon of the open reading frame. The 5’-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, for example, ribosomal binding sites or a 5’-Terminal Oligopyrimidine Tract. The 5’-UTR may be posttranscriptionally modified, for example by addition of a 5’-CAP. In the context of the present invention, a 5’-UTR corresponds to the sequence of a mature mRNA, which is located between the 5’-CAP and the start codon. Preferably, the 5’-UTR corresponds to the sequence, which extends from a nucleotide located 3’ to the 5’-CAP, preferably from the nucleotide located immediately 3’ to the 5’-CAP, to a nucleotide located 5’ to the start codon of the protein coding region, preferably to the nucleotide located immediately 5’ to the start codon of the protein coding region. The nucleotide located immediately 3’ to the 5’-CAP of a mature mRNA typically corresponds to the transcriptional start site. The term "corresponds to" means that the 5’-UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 5’- UTR sequence, or a DNA sequence, which corresponds to such RNA sequence. In the context of the present invention, the term "a 5’-UTR of a gene", such as "a 5’-UTR of a TOP gene", is the sequence, which corresponds to the 5’-UTR of the mature mRNA derived from this gene, i.e. the mRNA obtained by transcription of the gene and maturation of the premature mRNA. The term "5’-UTR of a gene" encompasses the DNA sequence and the RNA sequence of the 5’-UTR. Preferably, the 5’-UTR used according to the present invention is heterologous to the coding region of the mRNA sequence. Even if 5’-UTRs derived from naturally occurring genes are preferred, also synthetically engineered UTR’s may be used in the context of the present invention. 3’-untranslated region (3’-UTR): In the context of the present invention, a 3’-UTR is typically the part of an mRNA, which is located between the protein coding region (i.e. the open reading frame) and the 3’-terminus of the mRNA. A 3’-UTR of an mRNA is not translated into an amino acid sequence. The 3’-UTR sequence is generally encoded by the gene, which is transcribed into the respective mRNA during the gene expression process. In the context of the present invention, a 3’-UTR corresponds to the sequence of a mature mRNA, which is located 3’ to the stop codon of the protein coding region, preferably immediately 3’ to the stop codon of the protein coding region, and which extends to the 5’-side of the 3’-terminus of the mRNA or of the poly(A) sequence, preferably to the nucleotide immediately 5’ to the poly(A) sequence. The term "corresponds to" means that the 3’-UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 3’-UTR sequence, or a DNA sequence, which corresponds to such RNA sequence. In the context of the present invention, the term "a 3’-UTR of a gene", such as "a 3’- UTR of an albumin gene", is the sequence, which corresponds to the 3’-UTR of the mature mRNA derived from this gene, i.e., the mRNA obtained by transcription of the gene and maturation of the pre-mature mRNA. The term "3’-UTR of a gene" encompasses the DNA sequence and the RNA sequence of the 3’-UTR. Preferably, the 3’-UTR used according to the present invention is heterologous to the coding region of the mRNA sequence. Even if 3’-UTR’s derived from naturally occurring genes are preferred, also synthetically engineered UTR’s may be used in the context of the present invention. RNA in vitro transcription: The term "RNA in vitro transcription" (or ’in vitro transcription’) relates to a process wherein RNA, in particular mRNA, is synthesized in a cell-free system (in vitro). Preferably, cloning vectors, particularly plasmid DNA vectors are applied as template for the generation of RNA transcripts. These cloning vectors are generally designated as transcription vector. RNA may be obtained by DNA dependent in vitro transcription of an appropriate DNA template, which according to the present invention is preferably a linearized plasmid DNA template. The promoter for controlling RNA in vitro transcription can be any promoter for any DNA dependent RNA polymerase. Particular examples of DNA dependent RNA polymerases are the T7, T3, and SP6 RNA polymerases. A DNA template for RNA in vitro RNA transcription may be obtained by cloning of a nucleic acid, in particular cDNA corresponding to the respective RNA to be in vitro transcribed, and introducing it into an appropriate vector for RNA in vitro transcription, for example in plasmid circular plasmid DNA. The cDNA may be obtained by reverse transcription of mRNA or chemical synthesis. Moreover, the DNA template for in vitro RNA synthesis may also be obtained by gene synthesis. Preferably cloning vectors are used for RNA in vitro RNA transcription, which are generally designated transcription vectors. Chemical synthesis process: The term "chemical synthesis process " (or “DNA or RNA chemical synthesis) relates to an alternative process for obtaining RNA, usually using a solid phase method. Kozak sequence: As used herein, the term ’Kozak sequence’ typically refers to a sequence on an mRNA molecule, which is recognized by the ribosome as the translational start site of a protein encoded by that mRNA molecule. In a preferred embodiment, that sequence may comply with a consensus sequence for a nucleotide sequence mediating initiation of translation, preferably with the consensus sequence (gcc)gccRccAUGG (SEQ ID NO:44), wherein a lower case letter denotes the most common base at a position where the base can nevertheless vary; upper case letters indicate highly conserved bases, ’AUGG’; ’R’ indicates that a purine (adenine or guanine, preferably adenine) is present at this position; and the sequence in brackets is of uncertain significance. Open reading frame: An open reading frame (ORF) in the context of the invention may typically be a sequence of several nucleotide triplets, which may be translated into a peptide or protein. An open reading frame preferably contains a start codon, i.e. a combination of three subsequent nucleotides coding usually for the amino acid methionine (ATG), at its 5’-end and a subsequent region, which usually exhibits a length which is a multiple of 3 nucleotides. An ORF is preferably terminated by a stop-codon (e.g., TAA, TAG, TGA). Typically, this is the only stop-codon of the open reading frame. Thus, an open reading frame in the context of the present invention is preferably a nucleotide sequence, consisting of a number of nucleotides that may be divided by three, which starts with a start codon (e.g. ATG) and which preferably terminates with a stop codon (e.g., TAA, TGA, or TAG). The open reading frame may be isolated or it may be incorporated in a longer nucleic acid sequence, for example in a vector or an mRNA. An open reading frame may also be termed "protein coding region". Target cell: The term "target cell" as used herein may refer to a cell in which the deficient expression of GM-CSF protein causes a detectable disease phenotype. In particular a target cell may be a immune system cell, more particularly a macrophage and even more particularly a alveolar macrophage, for example in a patient suffering from aPAP. At least a portion of the nucleic acids of the invention are delivered to said target cell. Cell activation: The term "activation " as used herein may refer to classical (M1) or alternative (M2) immunological cell activation. Classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, extracellular matrix (ECM) destruction, and apoptosis, while alternatively activated macrophages display a Th2-like phenotype, promoting ECM construction, cell proliferation, and angiogenesis. Although both phenotypes are important components of both the innate and adaptive immune systems, the classically activated macrophage tends to elicit chronic inflammation and tissue injury whereas the alternatively activated macrophage tends to resolve inflammation and facilitate wound healing. Preferably, the activation is an alternative cell activation. Expansion: The term "expansion" as used herein may refer to an increase in cell numbers. Subject / Patient: As used herein, the term “subject” or “patient”, which are used interchangeably, refers to any individual, such as a mammal, without limitation, including humans and other primates (e.g., chimpanzees, cynomologous monkeys, and other apes and monkey species), farm animals (e.g., cattle, sheep, pigs, goats and horses), domestic mammals (e.g., dogs and cats), laboratory animals (e.g., rabbits, rodents such as mice, rats, and guinea pigs), and birds (e.g., domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like). In preferred embodiments, the subject is a human. In the sense of the present invention any individual suffering from a GM-CSF deficiency and/or GM-CSF related disease may be a subject and/or patient. In a preferred embodiment, a patient in the sense of the present invention may produce antiGM-CSF autoantibodies, GM-CSF neutralizing antibodies, antiGM-CSF receptor autoantibodies or GM-CSF receptor neutralizing antibodies. In a preferred embodiment, a patient may be an individual suffering from PAP or autoimmune PAP. In a preferred embodiment, a patient may be an individual suffering from PAP or autoimmune PAP caused by or partially caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in the patient, antiGM-CSF receptor autoantibodies or GM-CSF receptor neutralizing antibodies. GM-CSF deficiency and/or synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein deficiency, as well as related diseases and disorders: In its broadest sense the term “GM-CSF deficiency” means that a subject cannot produce GM- CSF in a sufficient amount to ensure proper biological function of GM-CSF. In particular, the term can mean that a subject produces less GM-CSF compared to a subject in a normal state, i.e. a wild-type and/or healthy subject. Accordingly, in a subject suffering from a GM-CSF deficiency, the biological function of GM-CSF may not function or not function properly when compared to a subject in a normal state, i.e. a wild-type and/or healthy subject. The term “GM-CSF deficiency” as used herein, thus, can refer to a condition in which a patient does not express sufficient GM- CSF, to achieve normal biological function, such as GM-CSF binding the GM-CSF receptor or if binding occurs, does not bind said receptor in an amount that induces a detectable activation of GM-CSF downstream targets. In general, a GM-CSF deficiency may be treated by increasing the GM-CSF level, such as increasing GM-CSF expression, in a subject. Accordingly, a GM-CSF deficiency may be a pathological condition that can be ameliorated by increasing GM-CSF expression. GM-CSF receptor activation may be monitored measuring the phosphorylation status of downstream targets such as STAT, as disclosed herein. A GM-CSF deficiency may be caused by insufficient GM-CSF levels (insufficient production or enhanced GM-CSF degradation or presence of antiGM-CSF antibodies such as autoantibodies or GM-CSF neutralizing antibodies) or in cases where normal GM-CSF levels are present by insufficient levels or activity of GM-CSF receptor (due to receptor mutations or presence of autoantibodies against said receptor). In a preferred embodiment, a GM-CSF deficiency may be caused by or partially caused by antiGM- CSF autoantibodies or GM-CSF neutralizing antibodies. In a preferred embodiment, a GM-CSF deficiency may be caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in a patient/subject. In a preferred embodiment, a GM-CSF deficiency is PAP or autoimmune PAP. In a preferred embodiment, a GM-CSF deficiency is PAP or autoimmune PAP caused by or partially caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in a patient/subject. The explanations provided herein above in relation to a “GM-CSF deficiency” and/or a related and/or thereby caused disease or disorder apply, mutatis mutandis, to any one of a synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein deficiency, a synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein related disease or a disease caused by a synthetase, GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency e.g. in a subject or patient. In accordance with the above, the invention is, inter alia, directed to the use of the herein provided nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein or any functional fragment thereof in the therapy (treatment and/or prevention) or any such GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF, and/or citrullinated protein deficiencies and/or related/thereby caused diseases and disorders, particularly of diseases and disorders associated/linked with/ characterized by (the presence of) autoantibodies (autoimmune diseases), specifically interstitial lung disease (ILD), PAP and aPAP, particularly wherein the diseases and disorders, specifically interstitial lung disease (ILD), PAP and aPAP, are associated/linked with/characterized by (the presence of) autoantibodies, such as anti-GM-CSF, anti-synthetase, anti-MDA5, Anti-Scl70, Anti-eIF2B, Anti-PM/Scl, Anti-Ku, Anti- Topo I, Anti-Th/To, Anti-U11/U12 RNP, Anti-U1RNP, Anti-RF and/or ACPA autoantibodies. Accordingly, a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency, as well as related diseases and disorders, may in some embodiment be selected from the list of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non- tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. Terms like “diseases and disorders associated/linked with/ characterized by (the presence of) autoantibodies” also refers to and includes subjects of patients suffering or prone to suffering from such diseases and disorders. For example, a “patient in need of treatment characterized for being positive to the presence of autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies, anti-synthetase, anti-MDA5, Anti-Scl70, Anti-eIF2B, Anti-PM/Scl, Anti-Ku, Anti-Topo I, Anti-Th/To, Anti-U11/U12 RNP, Anti-U1RNP, Anti-RF and/or ACPA autoantibodies” likewise refers to “diseases and disorders associated/linked with/ characterized by (the presence of) autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies, anti-synthetase, anti-MDA5, Anti-Scl70, Anti-eIF2B, Anti-PM/Scl, Anti-Ku, Anti-Topo I, Anti-Th/To, Anti-U11/U12 RNP, Anti-U1RNP, Anti-RF and/or ACPA autoantibodies”, and vice versa. The term “ACPA autoantibodies” (or short “ACPA”) and “anti-citrullinated protein antibodies” are used interchangeably herein. Accordingly, in one embodiment a disease wherein the subject is characterized for being positive to the presence of antiGM-CSF/antiGM-CSF, anti-synthetase, anti-MDA5, anti-Scl70, anti-eIF2B, anti-PM/Scl, anti-Ku, anti-Topo I, anti-Th/To, anti-U11/U12 RNP, anti-U1RNP, anti-RF and/or ACPA autoantibodies or the presence of to antiGM-CSF/antiGM-CSF receptor, anti-synthetase receptor, anti-MDA5 receptor, anti-Scl70 receptor, anti-eIF2B receptor, anti-PM/Scl receptor, anti- Ku receptor, anti-Topo I receptor, anti-Th/To receptor, anti-U11/U12 RNP receptor, anti-U1RNP receptor, anti-RF receptor and/or ACPA receptor autoantibodies or neutralizing antibodies is selected from the list of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof, optionally wherein the disease is caused by or partially caused by the presence of said autoantibodies or receptor neutralizing antibodies in the patient. The term “synthetase” as used herein refers in particular to any one of histidyl t-RNA synthetase, threonyl-t-RNA synthetase, alanyl-t-RNA synthetase, isoleucyl-t-RNA synthetase, glycyl-t-RNA synthetase, asparaginyl-t-RNA synthetase, phenylalanyl-t-RNA synthetase and tyrosyl-t-RNA synthetase. MDA5, or melanoma differentiation-associated protein 5, is a sensor protein involved in the body's immune response to viral infections. It belongs to a class of proteins known as RIG-I-like receptors (RLRs), which are crucial for recognizing viral RNA within cells and initiating an antiviral immune response. MDA5 specifically detects viral double-stranded RNA (dsRNA), a form of RNA often produced during the replication of RNA viruses. Upon recognizing dsRNA, MDA5 activates signaling pathways that lead to the production of type I interferons and other cytokines, which are key molecules in the immune response against viruses. MDA5 is not only significant in virology but also in immunology: Autoantibodies against MDA5 are associated with certain autoimmune conditions, notably including dermatomyositis, a disease characterized by chronic muscle and skin inflammation. Patients with anti-MDA5 antibodies often have a distinct clinical subtype of dermatomyositis, which may include rapidly progressive interstitial lung disease (ILD). Aminoacyl-tRNA synthetases (synthetases), are enzymes crucial for protein synthesis. Antisynthetase antibodies are prominently featured in the anti-synthetase syndrome, a condition characterized by a combination of clinical features including interstitial lung disease (ILD), myositis (muscle inflammation), arthritis, fever, Raynaud's phenomenon, and mechanic's hands (cracked, rough skin on the hands). Antisynthetase antibodies might be anti-histidyl t-RNA synthetase (anti-Jo-1), anti-threonyl-t-RNA synthetase (anti-PL-7), anti-alanyl-t-RNA synthetase (anti-PL-12), anti-isoleucyl-t-RNA synthetase (Anti-OJ), anti-glycyl-t-RNA synthetase (anti-EJ), anti-asparaginyl-t-RNA synthetase (Anti-KS), anti-phenylalanyl-t-RNA synthetase (Anti-ZO), anti- tyrosyl-t-RNA synthetase (Anti-Ha). Scl-70, also known as topoisomerase I, is a nuclear enzyme that plays a critical role in DNA replication, transcription, and repair. The autoantibodies against Scl-70 are highly specific biomarkers for systemic sclerosis (SSc), particularly the diffuse cutaneous subtype of the disease, which is characterized by extensive skin fibrosis and severe organ involvement. The presence of anti-Scl-70 autoantibodies is associated with a more progressive course of systemic sclerosis and is indicative of a higher risk of developing ILD. Eukaryotic initiation factor 2B (eIF2B) is crucial for mRNA translation initiation, regulating protein synthesis under stress conditions, such as viral infections or nutrient deprivation. Dysregulation of eIF2B is implicated in a range of diseases, including vanishing white matter disease and various neurodegenerative disorders. Additionally, recent studies suggest a link between eIF2B activity and the progression of interstitial lung diseases (ILD), where aberrant protein synthesis contributes to pulmonary fibrosis and tissue remodeling. PM/Scl (Polymyositis/Scleroderma) is an autoantigen complex targeted in polymyositis and scleroderma, diseases that can include ILD as a manifestation. Ku is a DNA-binding protein that plays a role in DNA repair; autoantibodies against Ku are seen in systemic sclerosis and overlap syndromes with ILD. Topo I (Topoisomerase I) is an enzyme that helps manage DNA supercoiling during replication and transcription; anti-Topo I antibodies are a marker for diffuse systemic sclerosis, often associated with severe ILD. Th/To is a ribonucleoprotein complex involved in RNA processing; antibodies against Th/To are typically seen in patients with scleroderma and are associated with pulmonary hypertension and ILD. U11/U12 RNP (U11/U12 Small Nuclear Ribonucleoproteins) are components of the minor spliceosome, involved in the splicing of a subset of pre-mRNA molecules; related to rare autoimmune responses. U1RNP (U1 Ribonucleoprotein) is part of the spliceosomal complex involved in pre-mRNA splicing; autoantibodies against U1RNP are common in mixed connective tissue disease, which can include ILD. RF (Rheumatoid Factor): An antibody that targets the Fc region of IgG, prevalent in rheumatoid arthritis, which can manifest with pulmonary complications including ILD. Citrullinated proteins are proteins that have undergone a post-translational modification wherein the amino acid arginine is converted into citrulline. This change is catalyzed by a family of enzymes known as peptidylarginine deiminases (PADs). Citrullination alters the protein's structure and function, affecting its interactions with other proteins and its role in biological processes. The presence of antibodies that target proteins containing citrulline (ACPA) are strongly associated with rheumatoid arthritis and linked to the risk of developing ILD. In some embodiments the patient is positive for the presence of autoantibodies for GM-CSF, synthetase, MDA5, PM/Scl, Ku, topo I, Th/To, U11/U12 RNP, EIF2B, U1RNP, RF, and/or is positive for ACPA (Anti-Citrullinated Protein Antibodies), preferably the patient is positive for autoantibodies for GM-CSF, MDA5, Scl70 and/or eIF2B, most preferably for autoantibodies for GM-CSF. This patent application focuses on novel methods and compositions for detecting, quantifying, and inhibiting the effect of autoantibodies in clinical settings. By targeting these autoantibodies, our invention aims to offer a therapeutic strategy that mitigates the severe inflammatory or fibrotic processes associated with the presence of autoantibodies, thereby improving patient outcomes and quality of life. Cancer: The term “cancer” as used herein is commonly understood in the art. In some embodiments, the cancer is selected from the group consisting of skin cancer, such as melanoma, non-small cell lung cancer (NSCLC), Hodgkin’s lymphoma, bladder cancer, renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), breast cancer, Merkel cell carcinoma, hepatocellular carcinoma (HCC) and gastric cancer (GC). In preferred embodiments, the cancer is a lung cancer. Preferably non-small cell lung cancer (NSCLC). As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated. As used herein, the term “or” is generally employed in its usual sense including “and/or” unless the content clearly dictates otherwise. The term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements. As used herein, the term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s). In some embodiments any one of the methods or uses described herein can be in vitro and/or ex vivo or in vivo. In some embodiments any of the method steps described herein can be in vitro and/or ex vivo or in vivo. The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease. In the sense of the present invention a desired pharmacological and/or physiological effect can be to increase GM-CSF levels to a level of a healthy and/or wild type individual. The term "treatment" as used herein covers any treatment of a disease in a subject and includes: (a) preventing a disease related to an insufficient immune response from occurring in a subject which may be predisposed to the disease; (b) inhibiting the disease, i.e. arresting its development; or (c) relieving the disease, i.e. causing regression of the disease. The disclosures in context of the methods described herein are disclosed as corresponding use mutatis mutandis. The disclosures in context of the use described herein are disclosed as corresponding methods mutatis mutandis. In one aspect, the methods of the present invention are not methods for treatment of the human or animal body by therapy. In a further aspect, the methods of the present invention are not processes for modifying the germ line genetic identity of human beings. In one aspect, the methods of the present invention are in vitro or ex vivo methods. In a further aspect, the methods of the present invention are not processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal. List of abbreviations ASLF airway surface lining fluid BALF bronchoalveolar lavage fluid GM-CSF granulocyte-macrophage colony stimulating factor GAPDH Glycerinaldehyd-3-phosphat-Dehydrogenase hGM-CSF Human Granulocyte/Macrophage-Colony Stimulating Factor mGM-CSF murine Granulocyte/Macrophage-Colony Stimulating Factor Formulation I composition in which the lipidoid of Formula (b-VI) is formulated with the lipids DPPC, cholesterol and PEG-lipid DMG-PEG2000 at the molar ratios 8:5.29:4.41:0.88 LNP Lipid Nanoparticle LiNP Lipidoid Nanoparticle mAb Monoclonal antibody mRNA Messenger ribonucleic acid pAb Polyclonal antibody PAP Pulmonary Alveolar Proteinosis STAT5 Signal Transducer and Activator of Transcription 5, a downstream molecule of the GM-CSF receptor used to measure GM-CSF biological activity pSTAT5 Phosphorylated STAT5 (activated STAT5) rec. Recombinant Nucleic acids One aspect of the present invention relates to a nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the nucleic acid comprises a nucleic acid sequence having at least a 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In an embodiment the GM-CSF is a human GM-CSF. In some embodiments, the mRNA is a codon optimized GM-CSF. In a preferred embodiment the nucleic acid comprises a nucleic acid sequence having at least a 95% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, more preferably at least 96% identity, at least 97% identity, at least 98% identity, or at least 99%. In the even more preferred embodiment, the nucleic acid comprises the sequence of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In an embodiment, the nucleic acid consists of the sequence defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In a most preferred embodiment the nucleic acid is the nucleic acid of SEQ ID NO:1 or SEQ ID NO:45. In an embodiment the GM-CSF is a murine GM-CSF. In an embodiment, the nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof comprises a nucleic acid sequence having at least a 94% identity to SEQ ID NO:9, SEQ ID NO:47, SEQ ID NO:12, or SEQ ID NO:49. In some embodiments the nucleic acid comprises a nucleic acid sequence having at least a 95% identity to SEQ ID NO:9, SEQ ID NO:47, SEQ ID NO:12, or SEQ ID NO:49, more preferably at least 96% identity, at least 97% identity, at least 98% identity, or at least 99%. In the most preferred embodiment, the nucleic acid comprises the sequence of SEQ ID NO:9, SEQ ID NO:47, SEQ ID NO:12, or SEQ ID NO:49. In certain embodiments, the nucleic acid according to the invention is selected from of a polynucleotide DNA molecule or a polynucleotide RNA molecule (polyribonucleotide). In some embodiments, the DNA or RNA is a vector, preferably a viral vector. In preferred embodiments, said polynucleotide is a polyribonucleotide molecule, more preferred is an mRNA molecule. Most preferably, the nucleic acid is a modified nucleic acid, such as a modified RNA or mRNA. In preferred embodiments, the term modified nucleic acid, is a nucleic acid with low immunogenicity. Immunogenicity can be determined in a manner known per se. Various methods well known to those skilled in the art can be used to determine the immunogenicity of a nucleic acid. A well-suited method is the determination of inflammatory markers in cells in response to the administration of nucleic acids such as RNA. Such a method is described in WO 2011012316 A2 and in particular in examples 3 to 5 therein. WO 2011012316 A2 is incorporated herein by reference in its entirety. Usually measured are cytokines which are associated with inflammation, e.g. TNF-α, IFN-α, IFN-β, IL-8, IL-6, IL-12, or other cytokines known to those skilled in the art. Expression of DC activation markers can also be used to assess immunogenicity. Another indication of an immunological reaction is evidence of binding to the Toll-like receptors TLR-3, TLR-7, TLR-8 or RIG-I. Immunogenicity is usually determined in relation to a control. In a conventional method, cells are administered either the nucleic acid of the invention or an unmodified nucleic acid and the secretion of inflammatory markers is measured at a certain time interval in response to the administration of the RNA. As a standard to be compared, either unmodified nucleic acid can be used, in which case the immune response would be higher, or a nucleic acid which is known to cause little or no immune response, in which case the immune response of the nucleic acid according to the invention is within the same range and should not be increased. With the nucleic acid according to the invention it is possible to decrease the immune response by at least 30%, usually at least 50%, 75% or lower or even may be completely prevented, i.e. that the immune response is decreased by 100% or absent in a cell or is comparable with an immune response in a cell not contacted by a nucleic acid. The immunogenicity of a nucleic acid can be determined by measuring the factors mentioned above, in particular the measurement of TNF-α and IL-8 levels and the binding ability to TLR-3, TLR-7, TLR-8 and helicase RIG1. Thus, to determine if a nucleic acid of the invention such as an mRNA has the desired low immunogenicity, the amount of one or more of the above factors may be measured after administration of the particular polyribonucleotide. Thus, e.g. Mice via the tail vein or i.p. an amount of mRNA to be tested is administered and then one or more of the above- mentioned factors in the blood after a predetermined period, e.g. be determined after 7 or 14 days. The amount of factor is then related to the amount of factor present in the blood of untreated animals. It has proved to be very valuable for the determination of immunogenicity to determine the binding ability to TLR-3, TLR-7, TLR-8 and / or helicase RIG-1. Very good indications are also provided by the TNF-α levels and IL-8 levels. Preferably, a nucleic acid according to the invention can be defined as low immunogenic if its binding ability to TLR-3, TLR-7, TLR-8 and RIG-1 is reduced by at least 50% compared to unmodified nucleic acid such as RNA. More preferably a low immunogenic nucleic acid is a nucleic acid wherein the binding to TLR-3, TLR-7, TLR-8 and RIG-1 is reduced by 75% or even by 80%. In preferred embodiments, the binding ability of TLR- 3, TLR-7, TLR-8, and RIG-1 is in the same range for the nucleic acid of the of the invention and for animals not treated with a control nucleic acid such as mRNA. In other words, the nucleic acid according to the invention causes virtually no inflammatory or immunological reactions. In any case, the RNA according to the invention has such low immunogenicity that the general health of the patient is not affected. Therefore, a small increase in the above-mentioned factors can be tolerated as long as the general condition does not deteriorate. Further properties of the mRNA according to the invention are its efficiency and stability. For this purpose, transcription efficiency, transfection efficiency, translation efficiency and duration of protein expression are important and can be determined by methods known per se. Accordingly, the invention provides in one aspect a modified nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, wherein the modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic. In a further aspect, the invention provides a modified nucleic acid encoding GM-CSF or a functional fragment thereof or a pharmaceutical composition or a cell according to the invention for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient, wherein the modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non- immunogenic. In a further aspect, the invention provides a modified nucleic acid encoding GM-CSF or a functional fragment thereof or a pharmaceutical composition or a cell according to the invention for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient, wherein the modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non- immunogenic, and wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. In a further aspect, the invention provides a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof; wherein the nucleic acid comprises one or more sequences encoding GM-CSF or a functional fragment thereof being delivered to and expressed in a target cell comprising a GM-CSF receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling), wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic. In a further aspect, the invention provides a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof; wherein the nucleic acid comprises one or more sequences encoding GM-CSF or a functional fragment thereof being delivered to and expressed in a target cell comprising a GM-CSF receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling), wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic, and wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. In some embodiments of the present invention, the polynucleotide, e.g. a polyribonucleotide, employed according to the present invention may contain a combination of unmodified and modified nucleosides. Modified nucleosides also include nucleosides that are synthesized post- transcriptionally by covalent modification of the nucleosides. Further, any suitable mixture of non- modified and modified nucleotides is possible. A modified polynucleotide may also contain modified nucleotides that replace all canonical nucleotides with a specific base. For example, all canonical uridines may be replaced with a modified uridine, e.g. N1-methylpseudouridine. This applies mutatis mutandis to any other nucleotides and modified nucleotides in a polynucleotide disclosed herein. A non-limiting number of examples of modified nucleotides/nucleosides can be found in the literature (e.g. Cantara et al., Nucleic Acids Res, 2011, 39(Issue suppl_1):D195- D201; Helm and Alfonzo, Chem Biol, 2014, 21(2):174-185; Carell et al., Angew Chem Int Ed Engl, 2012, 51(29):7110-31, incorporate herein by reference in their entirety) and some preferable modified nucleotides are mentioned exemplarily in the following based on their respective nucleoside residue: 1-methyladenosine, 2-methylthio-N6-hydroxynorvalyl carbamoyladenosine, 2-methyladenosine, 2’-O-ribosylphosphate adenosine, N6-methyl-N6-threonylcarbamoyladenosine, N6- acetyladenosine, N6-glycinylcarbamoyladenosine, N6-isopentenyladenosine, N6- methyladenosine, N6-threonylcarbamoyladenosine, N6,N6-dimethyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, N6-hydroxynorvalylcarbamoyladenosine, 1,2’-O- dimethyladenosine, N6,2’-O-dimethyladenosine, 2’-O-methyladenosine, N6,N6,2’-O- trimethyladenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6- methyladenosine, 2-methylthio-N6-isopentenyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6-2-methylthio-N6-threonyl carbamoyladenosine, 2-methylthio-N6-(cis- hydroxyisopentenyl)adenosine, 7-methyladenosine, 2-methylthio-adenosine, 2-methoxy- adenosine, 2’-amino-2’-deoxyadenosine, 2’-azido-2’-deoxyadenosine, 2’-fluoro-2’- deoxyadenosine, 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenosine, 7-deaza-8-aza- adenosine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine; 2-thiocytidine, 3-methylcytidine, N4-acetylcytidine, 5- formylcytidine, N4-methylcytidine, 5-methylcytidine, 5-hydroxymethylcytidine, 5-hydroxycytidine, lysidine, N4-acetyl-2’-O-methylcytidine, 5-formyl-2’-O-methylcytidine, 5,2’-O-dimethylcytidine, 2- O-methylcytidine, N4,2’-O-dimethylcytidine, N4,N4,2’-O-trimethylcytidine, isocytidine, pseudocytidine, pseudoisocytidine, 2-thio-cytidine, 2’-methyl-2’-deoxycytidine, 2’-amino-2’- deoxycytidine, 2’-fluoro-2’-deoxycytidine, 5-iodocytidine, 5-bromocytidine, 2’-azido-2’- deoxycytidine, 2’-amino-2’-deoxycytidine, 2’-fluor-2’-deoxycytidine, 5-aza-cytidine, 3-methyl- cytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-5- methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-l-methyl-pseudoisocytidine, 4-thio-l-methyl-1- deaza-pseudoisocytidine, 1-methyl-l-deaza-pseudoisocytidine, 2-methoxy-cytidine, 2-methoxy-5- methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-l-methyl-pseudoisocytidine, zebularine,5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine; 1- methylguanosine, N2,7-dimethylguanosine, N2-methylguanosine, 2’-O-ribosylphosphate guanosine, 7-methylguanosine, hydroxywybutosine, 7-aminomethyl-7-deazaguanosine, 7- cyano-7-deazaguanosine, N2,N2-dimethylguanosine, N2,7,2’-O-trimethylguanosine, N2,2’-O- dimethylguanosine, 1,2’-O-dimethylguanosine, 2’-O-methylguanosine, N2,N2,2’-O- trimethylguanosine, N2,N2J-trimethylguanosine, Isoguanosine, 4-demethylwyosine, epoxyqueuosine, undermodified hydroxywybutosine, methylated undermodified hydroxywybutosine, isowyosine, peroxywybutosine, galactosyl-queuosine, mannosyl-queuosine, queuosine, archaeosine, wybutosine, methylwyosine, wyosine, 7- aminocarboxypropyldemethylwyosine, 7-aminocarboxypropylwyosine, 7- aminocarboxypropylwyosinemethylester, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio- guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6- thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, 8-oxo- guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, N1-methylguanosine, 2’-amino-3’-deoxyguanosine, 2’-azido- 2’-deoxyguanosine, 2’-fluoro-2’-deoxyguanosine, 2-thiouridine, 3-(3-amino-3- carboxypropyl)uridine, 3-methyluridine, 4-thiouridine, 5-methyl-2-thiouridine, 5- methylaminomethyluridine, 5-carboxymethyluridine, 5-carboxymethylaminomethyluridine, 5- hydroxyuridine, 5-methyluridine, 5-taurinomethyluridine, 5-carbamoylmethyluridine, 5- (carboxyhydroxymethyl)uridine methyl ester, dihydrouridine, 5-methyldihydrouridine, 5- methylaminomethyl-2-thiouridine, 5-(carboxyhydroxymethyl)uridine, 5-(carboxyhydroxymethyl)- 2′-O-methyluridine methyl ester, 5-(isopentenylaminomethyl)uridine, 5- (isopentenylaminomethyl)-2-thiouridine, 3,2’-O-dimethyluridine, 5-carboxymethylaminomethyl-2’- O-methyluridine, 5-carbamoylhydroxymethyluridine, 5-carbamoylmethyl-2’-O-methyluridine, 5- carbamoylmethyl-2-thiouridine, 5-methoxycarbonylmethyl-2’-O-methyluridine, 5- (isopentenylaminomethyl)-2’-O-methyluridine, 5,2’-O-dimethyluridine, 2’-O-methyluridine, 2’-O- methyl-2-thiorudine, 2-thio-2’-O-methyluridine, uridine 5-oxyacetic acid, 5- methoxycarbonylmethyluridine, uridine 5-oxyacetic acid methyl ester, 5-methoxyuridine, 5- aminomethyl-2-thiouridine, 5-carboxymethylaminomethyl-2-thiouridine, 5-methylaminomethyl-2- selenouridine, 5-methoxycarbonylmethyl-2-thiouridine, 5-taurinomethyl-2-thiouridine, pseudouridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, N1-methylpseudouridine, 3-methylpseudouridine, 2’-O-methylpseudouridine, 5-formyluridine, 5-aminomethyl-2- geranyluridine, 5-taurinomethyluridine, 5-iodouridine, 5-bromouridine, 2’-methyl-2’-deoxyuridine, 2’-amino-2’-deoxyuridine, 2’-azido-2’-deoxyuridine, 2’-fluoro-2’-deoxyuridine, inosine, 1- methylinosine, 1,2’-O-dimethylinosine, 2’-O-methylinosine, 5-aza-uridine, 2-thio-5-aza-uridine, 4- thio-pseudouridine, 2-thio-pseudouridine, 5-carboxymethyl-uridine, 1-carboxymethyl- pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 1-taurinomethyl-pseudouridine, 5- taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl- pseudouridine, 4-thio-l-methyl-pseudouridine, 2-thio-l-methyl-pseudouridine, 1-methyl-l-deaza- pseudouridine, 2-thio-1-methyl-l-deaza-pseudouridine, dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4- methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 1,2′-O-dimethyladenosine, 1,2′-O- dimethylguanosine, 1,2′-O-dimethylinosine, 2,8-dimethyladenosine, 2- methylthiomethylenethio- N6-isopentenyl-adenosine, 2-geranylthiouridine, 2-lysidine, 2-methylthio cyclic N6- threonylcarbamoyladenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, 2- methylthio-N6-hydroxynorvalylcarbamoyladenosine, 2-methylthio-N6- threonylcarbamoyladenosine, 2-selenouridine, 2-thio-2′-O-methyluridine, 2′-O-methyladenosine, 2′-O-methylcytidine, 2′-O-methylguanosine, 2′-O-methylinosine, 2′-O-methylpseudouridine, 2′-O- methyluridine, 2′-O-methyluridine 5-oxyacetic acid methyl ester, 2′-O- ribosyladenosinephosphate, 2′-O-ribosylguanosinephosphate, 3,2′-O-dimethyluridine, 3-(3- amino-3-carboxypropyl)-5,6-dihydrouridine, 3-(3-amino-3-carboxypropyl)pseudouridine, 5,2′-O- dimethylcytidine, 5,2′-O-dimethyluridine, 5-(carboxyhydroxymethyl)-2′-O-methyluridine methyl ester, 55-(isopentenylaminomethyl)-2′-O-methyluridine, 5-aminomethyl-2-geranylthiouridine, 5- aminomethyl-2-selenouridine, 5-aminomethyluridine, 5-carbamoylmethyl-2′-O-methyluridine, 5- carboxyhydroxymethyluridine, 5-carboxymethyl-2-thiouridine, 5-carboxymethylaminomethyl-2- geranylthiouridine, 5-carboxymethylaminomethyl-2-selenouridine, 5-carboxymethylaminomethyl- 2′-O-methyluridine, 5-cyanomethyluridine, 5-formyl-2′-O-methylcytidine, 5- methoxycarbonylmethyl-2′-O-methyluridine, 5-methylaminomethyl-2-geranylthiouridine, 7- aminocarboxypropyl-demethylwyosine, 7-methylguanosine, 8-methyladenosine, N2,2′-O- dimethylguanosine, N2,7,2′-O-trimethylguanosine, N2,7-dimethylguanosine, N2,N2,2′-O- trimethylguanosine, N2,N2,7-trimethylguanosine, N2,N2,7-trimethylguanosine , N4,2′-O- dimethylcytidine, N4,N4,2′-O-trimethylcytidine, N4,N4-dimethylcytidine, N4-acetyl-2′-O- methylcytidine, N6,2′-O-dimethyladenosine, N6,N6,2′-O-trimethyladenosine, N6- formyladenosine, N6-hydroxymethyladenosine, agmatidine, 2-methylthio cyclic N6- threonylcarbamoyladenosine, glutamyl-queuosine, guanosine added to any nucleotide, guanylylated 5′ end , hydroxy-N6-threonylcarbamoyladenosine; In preferred embodiments the chemically modified nucleoside or nucleotide is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1- methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5- iodo-citosine and combinations thereof; More preferably pseudo-uridine, N1-methyl-pseudo- uridine, 2´-fluoro-2´-deoxycytidine, 5-iodocytidine, 5-methylcytidine, 2-thiouridine, 5-iodouridine and/or 5-methyl-uridine and combinations thereof. In some embodiments, only the cytidine or deoxycytidine and the uridine or deoxyuridine are modified. In preferred embodiments, only the cytidines and uridines are modified nucleosides. In more preferred embodiments, the nucleic acid according to the invention comprises a combination of 2-thiouridine and 5-methylcytidine. In certain embodiments, the modified nucleic acid comprises as nucleoside at least one pseudouridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). In some embodiments 100% of uridines of a modified nucleic acid of the present invention are replaced with 100% pseudouridine (ψ). In certain embodiments, the modified nucleic acid does not comprise N1-Methylpseudouridine (N1- ψ). In certain embodiments, the modified nucleic acid comprises as nucleoside at least one N1- methyl-pseudouridine (N1-ψ). In some embodiments, the modified uridines are essentially all N1- methylpseudouridine. In some embodiments, the poly(ribo)nucleotide employed according to the present invention contains a 100% N1-Methylpseudouridine (N1-ψ). In some embodiments, 100% of the uridines of a poly(ribo)nucleotide employed according to the present invention are replaced with 100% N1-Methylpseudouridine (N1-ψ). In preferred embodiments, no nucleosides other than N1-methyl-pseudouridine are modified (in other words, the poly(ribo)nucleotide does not comprise other modified nucleosides than N1-methyl-pseudouridine). In some embodiments a nucleic acid of the present invention consists of canonical A, C and G nucleosides and N1- Methylpseudouridine (N1-ψ). In some embodiments, the modified nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine. Optionally, the modified nucleic acid comprises between 5% and 50% 2-thiouridine and/or 5-methylcytidine. In a preferred embodiment, the modified nucleic acid comprises 25% 2-Thiouridine and 25% 5-Methylcytidine. In preferred embodiments, no nucleosides other than 2-thiouridine and 5-methylcytidine are modified (in other words, the poly(ribo)nucleotide does not comprise other modified nucleosides than 2-thiouridine and 5- methylcytidine). In a preferred embodiment, the modified nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine. In a more preferred embodiment, the modified nucleic acid comprises at least 1% N1-methylpseudouridine, at least 10% N1-methylpseudouridine, or at least 50% N1-methylpseudouridine. In the most preferred embodiment, the modified nucleic acid comprises 100% N1-methylpseudouridine. In preferred embodiments, no nucleosides other than N1-methyl-pseudouridine are modified (in other words, the poly(ribo)nucleotide does not comprise other modified nucleosides than N1-methyl-pseudouridine). In a preferred embodiment, the modified nucleic acid comprises chemically modified nucleosides 5-Iodouridine (I₅U) and 5-Iodocytidine (I₅C). In a more preferred embodiment, the modified nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine. In a more preferred embodiment, the modified nucleic acid comprises between 20%-40% 5-Iodouridine and between 2%-5% 5-Iodocytidine. In the most preferred embodiment, the modified nucleic acid comprises 30% 5-Iodouridine and 3% 5-Iodocytidine. In preferred embodiments, no nucleosides other than 5-Iodouridine and 5-Iodocytidine are modified (in other words, the poly(ribo)nucleotide does not comprise other modified nucleosides than 5-Iodouridine and 5-Iodocytidine). Furthermore, the term “modified nucleotide” comprises nucleotides containing isotopes such as deuterium. The term "isotope" refers to an element having the same number of protons but different number of neutrons resulting in different mass numbers. Thus, isotopes of hydrogen for example are not limited to deuterium but include also tritium. Furthermore, the polyribonucleotide can also contain isotopes of other elements including for example carbon, oxygen, nitrogen, and phosphor. It is also possible that modified nucleotides are deuterated or contain another isotope of hydrogen or of oxygen, carbon, nitrogen, or phosphor. The total number of modified nucleotide types in the polyribonucleotide can be 0, 1, 2, 3, or 4. Hence, in some embodiments, at least one nucleotide of one nucleotide type, e.g., at least one U nucleotide, can be a modified nucleotide. In some embodiments, at least one nucleotide of in total two nucleotide types, e.g. at least one U nucleotide and at least one C nucleotide, can be a modified nucleotide. In some embodiments, at least one nucleotide of in total three nucleotide types, e.g. at least one G nucleotide, at least one U nucleotide and at least one C nucleotide, can be a modified nucleotide. In some embodiments, at least one nucleotide of all four nucleotide types can be a modified nucleotide. In all these embodiments one or more nucleotides per nucleotide type can be modified, the percentage of said modified nucleotides of per nucleotide type being 0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the total percentage of modified nucleotides comprised in the mRNA molecules is 0%, 2.5%, 5 %, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments one or more of a canonical nucleotide type in a polynucleotide, such as adenine (A), uracil (U), guanine (G), or cytosine (C), is replaced with a modified nucleotide of the corresponding type. In some embodiments 0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of a canonical nucleotide type in a polynucleotide, such as adenine (A), uracil (U), guanine (G), or cytosine (C), is replaced with a modified nucleotide of the corresponding type. In some embodiments, 0%, 2.5%, 5 %, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of a canonical nucleotide type in a mRNA molecule is replaced with a modified nucleotide of the corresponding type. In some embodiments, all canonical nucleotides of one or more nucleotide types, such as adenine (A), uracil (U), guanine (G), or cytosine (C), are replaced with a modified nucleotide of the corresponding type in a mRNA. In a preferred embodiment the mRNA is an mRNA which contains a combination of modified and unmodified nucleotides. Preferably, it is an mRNA containing a combination of modified and unmodified nucleotides as described in WO 2011/012316 which is incorporated by reference herein in its entirety. The mRNA described therein is reported to show an increased stability and/or diminished immunogenicity. In a preferred embodiment, in such a modified mRNA 5% to 50% of the cytidine nucleotides and 5% to 50% of the uridine nucleotides are modified. In a preferred embodiment, in such a modified mRNA 5 to 50% of the canonical cytidine nucleotides and 5 to 50% of the canonical uridine nucleotides are replaced by modified nucleotides. The adenosine- and guanosine-containing nucleotides can be unmodified. The adenosine and guanosine nucleotides can be unmodified or partially modified, and they are preferably present in unmodified form. Preferably 10% to 35% of the cytidine and uridine nucleotides are modified and particularly preferably the content of the modified cytidine nucleotides lies in a range from 7.5 to 25% and the content of the modified uridine nucleotides in a range from 7.5 to 25%. It has been found that in fact a relatively low content, e.g., only 10% each, of modified cytidine and uridine nucleotides can achieve the desired properties. It is particularly preferred that the modified cytidine nucleotides are 5-methylcytidin residues and the modified uridine nucleotides are 2- thiouridin residues. Most preferably, the content of modified cytidine nucleotides and the content of the modified uridine nucleotides is 25%, respectively. In certain embodiments of any of the foregoing, the percentage of analogs of a given nucleotide refers to input percentage (e.g., the percentage of analogs in a starting reaction, such as a starting in vitro transcription reaction). In certain embodiments of any of the foregoing, the percentage of analogs of a given nucleotide refers to output (e.g., the percentage in a synthesized or transcribed compound). Both options are equally contemplated. In certain embodiments the nucleic acid is comprised in a vector, preferably an expression vector, more preferably the vector of SEQ ID NO:8, SEQ ID NO:75, SEQ ID NO:28 or SEQ ID NO:64. In preferred embodiments, the nucleic acid is an RNA molecule, preferably an mRNA molecule. The mRNA molecule may be produced recombinantly in in vivo systems by methods known to a person skilled in the art. Alternatively, the modified RNA molecule, preferably the mRNA molecules of the present invention may be produced in an in vitro system using, for example, an in vitro transcription system which is known to the person skilled in the art. An in vitro transcription system capable of producing RNA, preferably mRNA requires an input mixture of modified and unmodified nucleoside triphosphates to produce modified mRNA molecules. For example, a modified RNA of the present invention may be produced by in vitro transcription providing the desired modified nucleoside triphosphate instead of the canonical one. Canonical and modified nucleoside triphosphates may be combined in in vitro transcription reactions. Furthermore, the modified RNA molecule, preferably mRNA molecule, may be chemically synthesized, e.g., by conventional chemical synthesis on an automated nucleotide sequence synthesizer using a solid-phase support and standard techniques or by chemical synthesis of the respective DNA sequences and subsequent in vitro or in vivo transcription of the same. In an embodiment, the nucleic acid according to the invention is directly obtained by an in-vitro polymerase synthesis process or a chemical synthesis process, wherein the nucleotide reaction mixture utilized to synthetize the nucleic acid during the synthesis, or the synthesized nucleic acid contains a combination of unmodified and chemically modified nucleotides. A further aspect of the invention relates to a vector comprising the nucleic acid of the invention. In certain embodiments, the vector is an expression vector, more preferably a linearized expression vector. In preferred embodiments, the vector is the vector of SEQ ID NO:8 or SEQ ID NO:75. In some embodiments, the vector comprises the sequence defined in SEQ ID NO:8, SEQ ID NO:75, SEQ ID NO:28 or SEQ ID NO:64. In some embodiments, the vector consists of the sequence defined in SEQ ID NO:8, SEQ ID NO:75, SEQ ID NO:28 or SEQ ID NO:64. In certain embodiments the vector comprises a murine GM-CSF. Preferably, said murine GM-CSF vector is the vector of SEQ ID NO:13 or SEQ ID NO:31. The coding region comprised in the mRNA, and which encodes an GM-CSF protein can be a partly or fully codon optimized sequence. Codon optimization refers to a technique which is applied to maximize protein expression by increasing the translational efficiency of the respective polyribonucleotide as in some cases codons exist that are preferentially used by some species for a given amino acid. An example of a codon optimized coding region is the coding region depicted in SEQ ID NO:1, SEQ ID NO:45, SEQ ID NO:9, and SEQ ID NO:47. Further, said polyribonucleotide might comprise further modifications to adjust and/or extend the duration of expression. Said polyribonucleotide might also contain an m7GpppG cap, an internal ribosome entry site (IRES) and/or a poly(A) tail at the 3′ end and/or additional sequences for promoting translation. In addition, the polyribonucleotide employed according to the present invention may also comprise further functional regions and/or 3’ or 5’ non-coding regions. The 3’ and/or 5’ non-coding regions can be sequences which naturally flank the encoded protein or artificial sequences which contribute to the stabilization and/or regulation of said polyribonucleotide. Suitable sequences may be identified and investigated by routine experiments. Further, said polyribonucleotide can also have further functional regions and may be combined with regulatory elements and target sequences of micro-RNAs for example for spatial and temporal control the activity of the desired polyribonucleotide comprising a sequence which encodes a protein, i.e., for example with respect to specific cells or cell types and/or developmental stages or specific time frames. In one embodiment, the mRNA also contains a 5’- and/or 3’-UTR. In a particularly preferred embodiment, the UTR sequence is a 5’-UTR sequence as described in WO 2017/167910, which is incorporated by reference herein in its entirety. In some embodiments, the UTR is selected from the list consisting of: initiation domain of T7 promoter + minimal UTR-C + Kozak sequence (GGGAGACGCCACC (SEQ ID NO:3)), initiation domain of T7 promoter + minimal UTR-CT + Kozak sequence (GGGAGACTGCCACC, (SEQ ID NO:34)), CYBA 5´UTR (SEQ ID NO:15), 5´TISU UTR (GCCAAG), a combination of initiation domain of T7 promoter + minimal UTR-C + TISU as shown in SEQ ID NO:37), optionally directly upstream of the ATG as shown in SEQ ID NO:17, a combination of initiation domain of T7 promoter + minimal UTR-CT + TISU as shown in SEQ ID NO:35, optionally directly upstream of the ATG as shown in SEQ ID NO:25, human alpha globin 5´UTR (SEQ ID NO:18), 5´UTR of SEQ ID NO:19, a SP30 Spacer 5´ UTR (SEQ ID NO:21) and/or the 5’ UTR of SEQ ID NO:22. In some embodiments, the 5’UTR comprises an additional TISU element. Preferably, the mRNA contains a 5’-UTR sequence directly upstream of the start codon of the coding region which shows the following sequence: GGGAGACGCCACC (SEQ ID NO:3) or a 5’-UTR consisting of GGGAGACTGCCACC (SEQ ID NO:34). In a preferred embodiment, the mRNA comprises a 5’-UTR consisting of GGGAGACGCCACC (SEQ ID NO:3) In a further embodiment, the mRNA also contains a 3’-UTR, preferably a 3’-UTR selected from the list consisting of: 3’UTR of the sequence 5’-TTCG-3’, the UTR sequence 5’- CACCGGGCAATACGAGCTCAAGCCAGTCTC (SEQ ID NO:14), CYBA 3´UTR (SEQ ID NO:16), and/or 3’ UTR of SEQ ID NO:20. In another preferred embodiment, the mRNA is transcribed from a DNA molecule as described in WO 2017/167910 A1, incorporated by reference herein in its entirety. More preferably, such a DNA molecule comprises one strand with the following elements: (a) a coding region, including a start codon at its 5’ end, coding for an GM-CSF polypeptide; and (b) directly upstream of said coding sequence the sequence GGGAGACGCCACC (SEQ ID NOs:3, 46) or the sequence GGGAGACTGCCACC (SEQ ID NOs:34, 69) and upstream of this sequence a promoter which is recognized by a DNA-dependent RNA polymerase, preferably a promoter with the sequence TAATACGACTCACTATA (SEQ ID NO:4) which is recognized by a T7 DNA-dependent RNA polymerase. Thus, in such an embodiment the sequence upstream of the start codon of the coding region is TAATACGACTCACTATA GGGAGACGCCACC (SEQ ID NO:5) or TAATACGACTCACTATA GGGAGACTGCCACC (SEQ ID NOs:23, 59). The present invention also relates to an mRNA molecule comprising a sequence as shown in SEQ ID NO:6. SEQ ID NO:6 contains a transcription cassette comprising a 5’ UTR, a codon optimized coding region for human GM-CSF and a 3’ UTR. Moreover, the mRNA contains directly upstream of the start codon the sequence GGGAGACGCCACC (SEQ ID NO:3) and as a 3’-UTR the sequence 5’-TTCG-3’. Preferably, such an mRNA, after the in-vitro transcription further comprises a poly(A) tail, e.g., of about 120 nucleotides. In certain embodiments, the poly(A) tail is a segmented poly(A) tail. Segmented poly(A)s are disclosed in WO 2020074642 A1 which is incorporated by reference herein in its entirety. In some embodiments the segmented poly(A) comprises two poly(A) segments, each of 55 to 65 nucleotides long, separated by a segment of one to ten or 2 to 10 nucleotides, preferably 1 nucleotide or 6 nucleotides that are not As. In certain embodiments, the nucleic acid after the in-vitro transcription comprises SEQ ID NO:7 or SEQ ID NO:38. In some embodiments, the poly(A) is added after the in vitro transcription. Accordingly, the invention provides in one aspect a nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the nucleic acid comprises any of the following: (a1) a coding region, including a start codon at its 5’ end, coding for a codon optimized GM-CSF polypeptide having at least 94% identity to SEQ ID NO:1 or 45; and (a2) optionally a 5’ UTR upstream of said coding sequence, preferably wherein the 5’ UTR is a sequence selected from the list consisting of: the sequence GGGAGACGCCACC (SEQ ID NO:3 or 46), the sequence GGGAGACTGCCACC (SEQ ID NO:34 or 69), the sequence GGGAGACGCCAAG (SEQ ID NO:37 or 71), the sequence GGGAGACGCCAAG (SEQ ID NO:35 or 70), a CYBA 5´UTR (SEQ ID NO:15 or 51), 5´TISU UTR (GCCAAG), human alpha globin 5´UTR (SEQ ID NO:18 or 54), 5´UTR of SEQ ID NO:19 or 55, a SP30 Spacer 5´ UTR (SEQ ID NO:21 or 57) and/or the 5’ UTR of SEQ ID NO:22 or 58, and (a3) optionally upstream of (a2) a promoter which is recognized by a DNA-dependent RNA polymerase, preferably a promoter with the sequence TAATACGACTCACTATA (SEQ ID NO:4) which is recognized by a T7 DNA-dependent RNA polymerase, and (a4) optionally a 3’ UTR, preferably a 3’ UTR selected from 3’-UTR selected from the list consisting of: 3’UTR of the sequence 5’-TTCG-3’, the UTR sequence 5’- CACCGGGCAATACGAGCTCAAGCCAGTCTC (SEQ ID NO:14 or 50), CYBA 3´UTR (SEQ ID NO:16 or 52), and/or 3’ UTR of SEQ ID NO:20 or 56, and/or (a4) optionally a poly(A), preferably a segmented poly(A), preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In an embodiment, the nucleic acid is comprised in a vector, optionally a transcription or expression vector. In a particularly preferred embodiment, the mRNA is transcribed from a DNA molecule as shown in SEQ ID NOs: 8 or 75. The present invention also provides a DNA/RNA molecule comprising a sequence as shown in SEQ ID NO:8, SEQ ID NO:75, SEQ ID NO:28 or SEQ ID NO: 64. SEQ ID NO:8, SEQ ID NO:75, SEQ ID NO:28 or SEQ ID NO:64 show a DNA/RNA molecule for the transcription/after transcription of an mRNA molecule which encodes GM-CSF. In a preferred embodiment the nucleic acid comprises a nucleic acid sequence having at least a 95% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, more preferably at least 96% identity, at least 97% identity, at least 98% identity, or at least 99%. In the most preferred embodiment, the nucleic acid comprises the sequence of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In a preferred embodiment, the nucleic acid consists of the sequence defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. The mRNA which codes for GM-CSF can be combined with an mRNA which encodes further genes. In certain embodiments, the genes are immunomodulatory and/or immunostimulatory genes. In certain embodiments, the immunomodulatory gene is a cytokine, such as Interferon gamma or lambda. In a preferred embodiment, the immunomodulatory gene is interferon Lambda. In on embodiment the GM-CSF is a murine GM-CSF. In preferred embodiments, the nucleic acid comprising the murine GM-CSF comprises any one of SEQ ID NO:3-5 or 46. In one embodiment of the present invention relates to a nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, wherein the nucleic acid comprises a nucleic acid sequence having at least a 94% identity to SEQ ID NO:9, SEQ ID NO:47, SEQ ID NO:11 or SEQ ID NO:48. In one embodiment the nucleic acid encodes the protein of SEQ ID NO:10. In nucleic acids may be expressed from an in vitro transcription vector. In one embodiment the murine GM- CSF after in-vitro transcription is that of SEQ ID NO:12 or SEQ ID NO:49. In one embodiment the in-vitro transcription vector is the vector of SEQ ID NO:13. The nucleic acid of the present invention can be produced by in vitro transcription (IVT). When the nucleic acid of the present invention, such as the modified nucleic acid of the invention, is produced by in vitro transcription using a polymerase synthesis process, the nucleic acid is an RNA, preferably an mRNA, and/or the polymerase is a T7 polymerase. The features provided in the context of the nucleic acid of the present invention herein, apply to the nucleic acids used in methods, treatments, uses, or comprised in compositions, pharmaceutical compositions, cells or kits mutatis mutandis. As used herein the terms “nucleic acid” and “nucleic acid molecule” may be used interchangeably. Pharmaceutical compositions A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid encoding GM-CSF according to the invention. In certain embodiments, the composition comprises modified nucleic acid coding for GM-CSF or a functional fragment thereof. In certain embodiments, the pharmaceutical composition according to the invention comprises a nucleic acid as defined herein. In a preferred embodiment, the nucleic acid is an RNA, more preferably an mRNA. In a preferred embodiment, a pharmaceutical composition comprises the nucleic acid as defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In general, any of the nucleic acids disclosed herein can be comprised in a pharmaceutical composition. When a nucleic acid, such as a modified nucleic acid or modified mRNA, is comprised in a pharmaceutical composition, it may be modified as described herein. In particular, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the nucleic acid when being comprised in a pharmaceutical composition. In certain embodiments, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the nucleic acids, or the vectors according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of two or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, of the nucleic acids, or the vectors of the disclosure and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises a pool of the nucleic acids, or the vectors of the invention. In preferred embodiments, the nucleic acid comprises the modified nucleic acids as defined above under nucleic acids. In some embodiments, the pharmaceutical composition further comprises a therapeutic compound. In certain embodiments, the pharmaceutical composition further comprises a mucolytic agent, such as a hypertonic saline solution or a solution of N- acetylcysteine (NAC). In some embodiments, the pharmaceutical composition comprises one or more nucleic acids of the present invention formulated into a lipid nanoparticle, a liposome, or a virus-like particle. In the context of the present invention, the term "pharmaceutical composition" may refer to a composition comprising at least a nucleic acid, preferably a polyribonucleotide according to the present invention for administration to a subject in order to treat a GM-CSF deficiency. The polyribonucleotide is preferably included in an effective amount, i.e., an amount sufficient to induce a detectable therapeutic response in the subject to which the pharmaceutical composition is to be administered. The pharmaceutical composition of the invention can be in the form of a sterile aqueous or non-aqueous solution, suspension or emulsion or aerosol. Preferably, the pharmaceutical composition is in a form which allows administration to the respiratory system e.g., via inhalation, nebulization, via a spray or droplets, e.g., a nasal spray or nasal droplets. This is advantageous for the patients as an administration using a spray, droplets, a nebulizer or by inhalation can easily be done by the patient, is comfortable to transport and thus, easily available for the patient without restricting any freedom of action. The GM-CSF protein encoded by the nucleic acid comprised in the pharmaceutical composition can be any possible GM-CSF protein. Preferably said GM-CSF protein possesses a biological activity of GM-CSF. Said biological activities may be: bone-marrow production and differentiation of cells of the myeloid lineage, development and maintenance of pulmonary alveolar macrophages, recruitment and differentiation of monocyte-derived dendritic cells (DCs) including production of IL-23 and T_H17 polarization of T cells, conventional DC maturation and antigen presentation including CD103-expressing DCs in skin and small intestine, M1 macrophage polarization including proinflammatory cytokine production, phagocytosis, antigen presentation, neutrophil priming and activation including phagocytosis, oxidative burst and nitric oxide production, myeloid-cell vascular-wall adhesion, vessel-wall accumulation and tissue trafficking, breakdown of blood-brain barrier, and/or angiogenesis, tumor growth, lgM antibody production by IRA B cells, and/or nociception (via sensory neurons). In one embodiment the GM-CSF protein encoded by the nucleic acid, preferably a mRNA, comprised in the pharmaceutical composition is human GM-CSF, preferably GM-CSF comprising the amino acid sequence as shown in SEQ ID NO:2. In a more preferred embodiment the mRNA encoding GM-CSF comprises a coding region as shown in SEQ ID NO:1. In one embodiment the GM-CSF protein encoded by the mRNA comprised in the pharmaceutical composition is murine GM-CSF, preferably GM-CSF comprising the amino acid sequence as shown in SEQ ID NO:10. In a more preferred embodiment the mRNA encoding GM-CSF comprises a coding region as shown in SEQ ID NO:9. The mRNA which is to be administered in accordance with the present invention is in the form of a pharmaceutical composition. In accordance with this invention, the term “pharmaceutical composition” relates to a composition for administration to a subject. Exemplary subjects include a mammal such as a dog, cat, pig, cow, sheep, horse, rodent, e.g., rat, mouse, and guinea pig, or a primate, e.g., gorilla, chimpanzee, and human. In a most preferable embodiment, the subject is a human. Generally, the RNA is included in an effective amount in the pharmaceutical composition. The term "effective amount" refers to an amount sufficient to induce a detectable therapeutic response in the subject to which the pharmaceutical composition is to be administered. In certain embodiments, the pharmaceutical composition of the invention may further contain a nucleic acid encoding a protein or RNA other than GM-CSF. In one embodiment, said further nucleic acid encodes a cytokine, preferably interferon lambda or interferon gamma. The pharmaceutical composition can comprise a pharmaceutically acceptable carrier, i.e., chemical compounds, materials, ingredients, and/or compositions, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Thus, a pharmaceutically acceptable carrier is an inactive substance formulated alongside the pharmaceutically active substance for facilitating its handling in view of dosage, adsorption, absorption, solubility or pharmacokinetic considerations. Examples of suitable pharmaceutical acceptable carriers are well known in the art and include phosphate buffered saline solutions, buffer, water, emulsions, such as oil/water emulsions, various types of wetting agents, and sterile solutions. In particularly, aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Further examples of pharmaceutically acceptable carriers include but are not limited to saline, Ringer's solution and dextrose solution, citrate, phosphate, and other organic acids; salt-forming counter-ions, e.g. sodium and potassium; low molecular weight (> 10 amino acid residues) polypeptides; proteins, e.g. serum albumin, or gelatin; hydrophilic polymers, e.g. polyvinylpyrrolidone; amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine; carbohydrates including glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars, e.g. sucrose, mannitol, trehalose or sorbitol; chelating agents, e.g. EDTA; non-ionic surfactants, e.g., polyoxyethylene sorbitan monolaurate, available on the market with the commercial name Tween, propylene glycol, poloxamers such as Pluronic® or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and/or preservatives, e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol). Suitable pharmaceutically acceptable carriers and their formulations are described in greater detail in Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Co. Furthermore, preservatives, stabilizers and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases, nanosystems or liposomes, and the like. The administration of the mRNA encoding a GM-CSF protein for the treatment and/or prevention of a GM-CSF deficiency, and in particular a GM-CSF deficiency caused by autoantibodies or autologous cellular factors, such as autoimmune pulmonary alveolar proteinosis (PAP), can be achieved by means and methods known to the person skilled in the art, in particular for ensuring that the mRNA reaches the intended target tissue/target cells. Possible routes are, e.g., intravenous, intramuscular, intradermal, subcutaneous and delivery into the respiratory system. The administration into the respiratory system is preferred. Possibilities for delivery into the respiratory system include instillation and inhalation. Alternatively, for delivery of the mRNA into the lung, also an intravenous administration with formulations that have a tropism for the lung is possible. In a preferred embodiment, the pharmaceutical composition comprising the mRNA encoding a GM-CSF polypeptide is administered to a patient via inhalation. The mRNA can be inhaled in any form which is suitable for inhalation. In a preferred embodiment, the mRNA is present in the pharmaceutical composition in a form suitable for inhalation in the form of an aerosol. A particularly suitable way of administering the mRNA to the respiratory system of a patient is by nebulization. In a preferred embodiment, the inhalation is bolus inhalation. This means that during inhalation only for a short amount of time the aerosol containing the active agent is mixed to the inhaled air. If the aerosol containing the active agent is mixed with the air at the beginning of the inhalation, the active agent reaches with the first part of the inhaled air the deeper parts of the lung. If at the end of inhalation, the addition of the active agent is stopped, no active agent is deposited in the central region of the lung, i.e., the airways, at the end of the inhalation. By using bolus inhalation it is possible to better target the different regions of the lung, e.g. the periphery of the lung or the central region, as regards the deposition of the active agent, depending on the requirements of the underlying disease state. The nucleic acid of the invention can advantageously be combined in the pharmaceutical composition with compounds which ease delivery of the mRNA to the target cells or the target tissue and/or which increase its stability. One possibility in this regard is the formulation of the RNA with liposomes or lipids, optionally to generate nanoparticles with suitable substances such as those described herein and, e.g. in WO2020165352A1, which is incorporated herein in its entirety. In particular, the mRNA molecule of the invention might be formulated with liposomes to generate lipoplexes or later generations of lipid nanocarriers, such as lipid nanoparticles (LNPs), lipidoid nanoparticles (LiNPs), nanostructured lipid carriers, and/or cationic lipid–nucleic acid complexes. Optionally, the nucleic acid of the invention may be delivered using liposomal transfection reagents and/or lipid nanoparticles (LNPs). LTRs and LNPs/LiNPs show the following important differences: Composition: Liposomal transfection reagents are made up of cationic lipids (lipids that have a positive charge). When combined with nucleic acids, which have a negative charge, the cationic lipids can form liposomes that encapsulate the nucleic acids and protect them from degradation. LNPs, in contrast, are made up of a more complex mixture of lipids and other components, which can vary depending on the specific application. In addition to cationic lipids, LNPs may contain neutral or anionic lipids, cholesterol, and PEG. The presence of these additional components may improve the stability and efficacy of the LNPs, making them more efficient at delivering nucleic acids into cells. Structure: Liposomes formed by liposomal transfection reagents are typically larger than LNPs and have a simpler structure. They may be multilamellar (consisting of multiple concentric lipid bilayers), or unilamellar, (a single lipid bilayer). In contrast, LNPs are typically smaller in size and have a more complex structure. They may contain multiple layers of lipids and other components, as well as a core containing the nucleic acid cargo. Efficiency: While both liposomal transfection reagents and LNPs can be effective at delivering nucleic acids into cells, LNPs are generally considered to be more efficient. This is because they are able to protect the nucleic acid cargo from degradation by extracellular enzymes and improve its uptake by target cells. The PEG component of LNPs can also help to increase circulation time in the bloodstream, allowing the LNPs to reach their target cells more effectively. Applications: Liposomal transfection reagents are commonly used for in vitro applications, such as gene expression studies or drug discovery. They may also be used for in vivo applications in animal models, but they are generally not suitable for use in humans due to their potential toxicity and immunogenicity. In contrast, LNPs are being increasingly used for clinical applications, such as mRNA vaccines and gene therapies. LNPs have been shown to be safe and effective in human clinical trials, making them a promising option for delivering nucleic acid-based therapies. Thus, LTRs may be used for delivering and/or introducing the nucleic acid of the invention into a target cell or a target tissue. LTRs comprise an ionizable or permanently cationic lipid and optionally a helper lipid such as DOPE in aqueous suspension. The pharmaceutical composition may further comprise at least one lipid or liposomal transfection reagent or enhancer (LTR; liposomal transfection reagent). The nucleic acid and in particular the mRNA to be employed may be comprised in, complexed with and/or delivered by the LTR. In particular, the nucleic acid and in particular the mRNA to be employed may be comprised in and/or delivered by (respective) lipofection complexes comprising the nucleic acid and the LTR. The pharmaceutical composition may (further) comprise the lipofection complexes. Some examples of LTRs that can be used with the nucleic acids of the invention are: ^ Lipofectamine: Lipofectamine is a cationic lipid-based transfection reagent that is commonly used for the transfection of plasmid DNA and siRNA in vitro. It is composed of a mixture of cationic lipids, including 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]- N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA) and 1,2-Dioleoyl-sn- glycerophosphoethanolamine (DOPE). ^ Lipofectin™: Lipofectin is another cationic lipid-based transfection reagent that is used for the transfection of plasmid DNA and siRNA in vitro. It is composed of a mixture 1:1 of cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), and DOPE in water. ^ TransFast®: TransFast is a cationic lipid-based transfection reagent that is used for the transfection of plasmid DNA and siRNA in vitro. It is composed of a mixture of cationic lipids, including (+)-N,N [bis (2-hydroxyethyl)]-N-methyl-N- [2,3- di(tetradecanoyloxy)propyl] ammonium iodide and DOPE. ^ Lipofectamine MessengerMAX, which is a cationic lipid-based reagent that can efficiently deliver mRNA molecules into a wide variety of cell types. ^ TransIT-mRNA, which is based on a lipid/polymer hybrid structure that can deliver mRNA to both adherent and suspension cells. One particular mode for delivering and/or introducing the nucleic acid, and mRNA in particular into target cells or target tissue using the LTRs cited above is transfection. Hence, the mRNA to be employed can be envisaged to be transfected into target cells or tissues, to be delivered/administered via transfection and/or to be prepared for transfection. Means and methods for transfecting mRNA are well known in the art and are, for example, described in Yamamoto (Eur J Pharm Biopharm.71(3) (2009), 484-9) and Kormann (Nat Biotechnol. 29(2) (2011), 154-7). Particular modes of transfection are lipofection, magnetofection, magnetolipofection or complexation with polymers. Hence, the mRNA to be employed may be prepared for lipofection, prepared to be transfected by lipofection, delivered/introduced via lipofection and/or administered via lipofection. Alternatively, the nucleic acid of the invention can be delivered to target cells and/or target tissues in vivo, ex-vivo and/or in vitro using lipid nanoparticles (LNPs) or lipidoid nanoparticles (LiNPs). The production of LNPs/LiNPs involves a combination of lipids, such as phospholipids, cholesterol, and other specialized lipids, which are mixed together in a solvent, such as an alcohol. This mixture is then subjected to a process called nanoprecipitation, which involves rapidly mixing the lipid solution with a non-solvent, such as a nucleic acid dissolved in water, under controlled conditions of temperature, pressure, and stirring rate. During this process, the lipids self-assemble into complex nanoscale structures, which trap and protect the therapeutic nucleic acids of the invention inside. The nano particles may also be further modified with various surface coatings, such as polyethylene glycol (PEG), to improve their stability and reduce their tendency to be cleared by the immune system. The lipid and/or lipidoid nanoparticles may comprise component (a), and optionally components (b), (c) and/or (p) as described below. As component (a), the nanoparticles contained in the pharmaceutical composition of the invention, for example in the form of a formulation for aerosol formation, for intramuscular and/or subcutaneous administration, may comprise a nucleic acid coding for GM-CSF as described herein, which provides a pharmaceutically active ingredient of the nanoparticles. The nanoparticles of the aqueous suspension formulation in accordance with the invention may further comprise, as a component (b) an ionizable lipid or an ionizable lipidoid. It will be understood that this encompasses the possibility that the nanoparticles comprise a combination of different ionizable lipids, a combination of different ionizable lipidoids, or a combination of one or more ionizable lipids and one or more ionizable lipidoids. The nanoparticles used in the context of the present invention typically comprise a nucleic acid (a) and a ionizable lipid or the ionizable lipidoid (b) in the form of a mixture of these components. The terms “ionizable lipid” and “ionizable lipidoid”, are used in the field of lipid nanoparticles and lipidoid nanoparticles to refer to a lipid or a lipidoid which is protonated to carry a cationic charge, or which can be protonated to carry a cationic charge. Thus, ionizable lipids and lipidoids, respectively, are also referred to as “protonatable lipids” and “protonatable lipidoids”, or as titratable lipids or titratable lipidoids, respectively. As will be understood by the skilled reader, the reference to an “ionizable lipid” or an “ionizable lipidoid” encompasses the ionizable lipid or lipidoid in its protonated or non-protonated form. As will further be understood, the protonated or non- protonated state of the lipid or lipidoid is generally determined by the pH value of a medium surrounding the lipid or lipidoid, e.g. by the pH value of the aqueous vehicle solution comprised in the aqueous suspension formulation and by the aerosol in accordance with the invention. Counterions (anions) for the positive charges of positively charged ionizable lipids or ionizable lipidoids in the context of the invention are typically provided by anionic moieties contained in the nucleic acid. If positively charged groups are present in excess compared to the anionic moieties in the nucleic acid, positive charges may be balanced by other pharmaceutically acceptable anions, such as chloride, bromide, or iodide, sulfate, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate, carbonate, or hydrogencarbonate, or by a polyanion component different from the nucleic acid, which may be present as an optional component in the nanoparticles. Ionizable lipids and ionizable lipidoids are well known as components of lipid nanoparticles or lipidoid nanoparticles. In the context of the present invention, there are no particular restrictions imposed on the type of ionizable lipid or ionizable lipidoid contained in the nanoparticles. Generally, an ionizable lipid or lipidoid, respectively, comprises a primary, secondary or tertiary amino group which can act as proton acceptor and which may thus be protonated or non- protonated. An ionizable lipidoid generally comprises a plurality of such amino groups, such as two or more, preferably three or more. Preferably, an ionizable lipid which may be comprised by the nanoparticles used in the suspension formulation and in the aerosol in accordance with the invention is a lipid which comprises a protonatable head group which contains one or more, preferably one, primary, secondary or tertiary amino group(s) as a protonatable or protonated group, and one or more, preferably one or two, hydrophobic moieties, linked to the head group. Examples of these preferred ionizable lipids are i) a lipid which comprises a protonatable head group which contains one or more, preferably one, primary, secondary or tertiary amino group(s) as a protonatable or protonated group, and one hydrophobic moiety linked to the head group; ii) a lipid which comprises one secondary or tertiary amino group as a protonatable or protonated head group, and two hydrophobic moieties linked to the head group. A hydrophobic moiety comprised in these preferred lipids preferably contains one or more of a linear chain aliphatic residue, e.g. a linear chain residue comprising 8 to 18 carbon atoms, a branched chain aliphatic residue, e.g. a branched chain residue comprising 8 to 18 carbon atoms, or an alicyclic ring structure which may be a condensed ring structure, e.g. an alicyclic ring structure comprising 10 to 18 carbon atoms. In addition, the hydrophobic moiety may comprise one or more linking groups which facilitate the linking of the moiety to the head group, or which allow two or more of the above aliphatic residues to be combined with each other. Furthermore, it may comprise one or more substituents, to the extent that the hydrophobic characteristics of the moiety are maintained. Preferably, an ionizable lipidoid which may be comprised in the nanoparticles used in the suspension formulation and in the aerosol in accordance with the invention is an oligoamine, more preferably an oligoalkylamine, which comprises at least two, preferably at least three, amino groups selected from a protonatable or protonated secondary and a tertiary amino group, each of which may carry a hydrophobic moiety attached to it. In addition to the amino groups carrying a hydrophobic residue, the lipidoid may comprise further protonatable or protonated amino groups selected from a primary, a secondary and a tertiary amino group. Preferably, the total number of the amino groups is 3 to 10, more preferably 3 to 6. Preferably, the total number of hydrophobic moieties attached to the amino groups is 3 to 6. Preferably, the ratio of the number of hydrophobic moieties attached to amino groups to the total number of amino groups in the oligoalkylamine is 0.75 to 1.5 A hydrophobic moiety comprised in such a preferred lipidoid preferably contains one or more of a linear chain aliphatic residue, e.g. a linear chain residue comprising 8 to 18 carbon atoms and a branched chain aliphatic residue, e.g. a branched chain residue comprising 8 to 18 carbon atoms. In addition, the hydrophobic moiety may comprise one or more linking groups which facilitate the linking of the moiety to an amino group, or which allow two or more of the above aliphatic residues to be combined with each other. Furthermore, it may comprise one or more substituents, to the extent that the hydrophobic characteristics of the moiety are maintained. Suitable exemplary ionizable lipids or ionizable lipidoids which can be comprised as component (b1) in the in the nanoparticles used in the context of the present invention are disclosed, e.g., in WO 2006/138380 A2, EP2476756 A1, US 2016/0114042 A1, US 8,058,069 B2, US 8,492,359 B2, US 8,822,668 B2, US 8,969,535, US 9,006,417 B2, US 9,018,187 B2, US 9,345,780 B2, US 9,352,042 B2, US 9,364,435 B2, US 9,394,234 B2, US 9,492,386 B2, US 9,504,651 B2, US 9,518,272 B2, DE 19834683 A1, WO 2010/053572 A2, US 9,227,917 B2, US 9,556,110 B2, US 8,969,353 B2, US 10,189,802 B2, WO 2012/000104 A1, WO 2010/053572, WO 2014/028487 or WO 2015/095351, or by Akinc, A., et al., Nature Biotechnology, 26(5), 2008, 561-569; Sabnis, S. et al., Molecular Therapy, 26(6), 2018, Vol.26 No 6 June 2018, 1509-1519; Kowalski, P.S., et al., Molecular Therapy, 27(4), 2019, 710-728; Kulkarni, J. A. et al, Nucleic Acid Therapeutics, 28(3), 2018, 146-157; and Li, B. et al., Nano Letters, 15, 2015, 8099-8107. Preferably, component (b) of the nanoparticles comprises or more, preferably consists of, an ionizable lipidoid of the following formula (b-1) or a protonated form thereof. The ionizable lipidoid of the following formula (b-1) or its protonated forms can be used as a preferred component (b) in the context of the present invention are described in detail in the PCT application WO 2014/207231 A1. Thus, component (b) preferably comprises or consists of a lipidoid of the following formula (b-1)

wherein the variables a, b, p, m, n and R^1A to R^6A are defined as follows: a is 1 and b is an integer of 2 to 4; or a is an integer of 2 to 4 and b is 1, p is 1 or 2, m is 1 or 2; n is 0 or 1 and m+n is ≥ 2; and R^1A to R^6A are independently of each other selected from hydrogen; -CH₂-CH(OH)-R^7A, -CH(R^7A)- CH₂-OH, -CH₂-CH₂-(C=O)-O-R^7A, -CH₂-CH₂-(C=O)-NH-R^7A ; -CH₂-R^7A; -C(NH)-NH₂; a poly(ethylene glycol) chain; and a receptor ligand; wherein R^7A is selected from C3-C18 alkyl and C3-C18 alkenyl having one C-C double bond; provided that at least two residues among R^1A to R^6A are selected from -CH₂-CH(OH)-R^7A, -CH(R^7A)-CH₂-OH, -CH₂-CH₂-(C=O)-O-R^7A, -CH₂-CH₂-(C=O)-NH-R^7A and -CH₂-R^7A wherein R^7A is selected from C3-C18 alkyl or C3-C18 alkenyl having one C-C double bond; or a protonated form thereof, wherein one or more of the nitrogen atoms contained in the compound of formula (b-1) are protonated to provide a compound carrying a positive charge. Preferably, R^1A to R^6A are independently selected from hydrogen; a group CH(R^7A)-CH₂-OH, -CH₂-

selected from C3- C18 alkyl and C3-C18 alkenyl having one C-C double bond; provided that at least two residues among R^1A to R^6A, more preferably at least three residues among R^1A to R^6A, and still more preferably at least four residues among R^1A to R^6A are a group selected from -CH2-CH(OH)-R^7A, -CH(R^7A)-CH2-OH, -CH2-CH2-(C=O)-O-R^7A, -CH2-CH2-(C=O)-NH-R^7A and -CH2-R^7A wherein R^7A is selected from C3-C18 alkyl and C3-C18 alkenyl having one C-C double bond. More preferably, R^1A to R^6A are independently selected from hydrogen and a group -CH2-CH(OH)-R^7A wherein R^7A is selected from C3-C18 alkyl and C3-C18 alkenyl having one C-C double bond; provided that at least two residues among R^1A to R^6A, more preferably at least three residues among R^1A to R^6A, and still more preferably at least four residues among R^1A to R^6A are a group -CH2-CH(OH)-R^7A, wherein R^7A is selected from C3-C18 alkyl and C3-C18 alkenyl having one C-C double bond. Preferably, R^7A is selected from C8-C18 alkyl and C8-C18 alkenyl having one C-C double bond, and more preferably from C8-C12 alkyl and C8-C12 alkenyl having one C-C double bond. Generally, alkyl groups are preferred over alkenyl groups as R^7A. As far as any of the groups R^1A to R^6A is a protecting group for an amino group, such as described for example in WO2006/138380, preferred embodiments thereof are t-butoxycarbonyl (Boc), 9- fluorenylmethoxycarbonyl (Fmoc), or carbobenzyloxy (Cbz). As far as any of the groups R^1A to R^6A are a receptor ligand, useful examples are given in Philipp and Wagner in “Gene and Cell Therapy – Therapeutic Mechanisms and Strategy”, 3^rd Edition, Chapter 15. CRC Press, Taylor & Francis Group LLC, Boca Raton 2009. Preferred receptor ligands for lung tissue are described in Pfeifer et al. 2010, Ther Deliv. 1(1):133-48. Preferred receptor ligands include synthetic cyclic or linear peptides such as derived from screening peptide libraries for binding to a particular cell surface structure or particular cell type, cyclic or linear RGD peptides, synthetic or natural carbohydrates such as sialic acid, galactose or mannose or synthetic ligands derived from reacting a carbohydrate for example with a peptide, antibodies specifically recognizing cell surface structures, folic acid, epidermal growth factor and peptides derived thereof, transferrin, anti-transferrin receptor antibodies, nanobodies and antibody fragments, or approved drugs that bind to known cell surface molecules. As far as any of the groups R^1A to R^6A are a poly(ethylene glycol) chain, the preferred molecular weight of the poly(ethylene glycol) chain is 100 – 20,000 g/mol, more preferably 1,000 – 10,000 g/mol and most preferred is 1,000 – 5,000 g/mol. The variable p in formula (b-1) is preferably 1. In formula (b-1), m is 1 or 2; n is 0 or 1 and m+n is ≥ 2. In other words, if m is 1, n must also be 1, and if m is 2, n can be 0 or 1. If n is 0, m must be 2. If n is 1, m can be 1 or 2. The variable n in formula (b-1) is preferably 1. It is more preferred that m is 1 and n is 1. Thus, the combination of p = 1, m = 1 and n = 1 is likewise preferred. As for the variables a and b in formula (b-1), it is preferred that one of a and b is 1, and the other one is 2 or 3. It is more preferred that a is 1 and b is 2, or that a is 2 and b is 1. Most preferably, a is 1 and b is 2. In view of the above, it is further preferred that the compound of formula (b-1) is a compound of formula (b-1a) and that component (b) comprises or consists of a lipidoid of the following formula (b-1a): R^1A-NR^2A-CH₂-(CH₂)_a-NR^3A-CH₂-(CH₂)_b-NR^4A-CH₂-(CH₂)_a-NR^5A-R^6A (b-1a), wherein a, b, and R^1A to R^6A are defined as in formula (b-1), including preferred embodiments thereof; or a protonated form thereof wherein one or more of the nitrogen atoms indicated in formula (b- 1a) are protonated to provide a compound carrying a positive charge. In accordance with a still further preferred embodiment, the compound of formula (b-1) is a compound of formula (b-1b) and component (b) comprises or consists of a lipidoid compound of the following formula (b-1b),

wherein R^1A to R^6A are defined as in formula (b-1), including preferred embodiments thereof; or a protonated form thereof wherein one or more of the nitrogen atoms indicated in formula (b- 1b) are protonated to provide a compound carrying a positive charge. Thus, in a accordance with a particularly preferred embodiment, component (b) comprises or consists of a lipidoid compound of the above formula (b-1b) or a protonated form thereof, and R^1A to R^6A are independently selected from hydrogen and -CH₂-CH(OH)-R^7A, wherein R^7A is selected from C8-C18 alkyl and C8-C18 alkenyl having one C-C double bond, provided that at least two residues among R^1A to R^6A are -CH₂-CH(OH)-R^7A, more preferably at least three residues among R^1A to R^6A, and still more preferably at least four residues among R^1A to R^6A are -CH₂-CH(OH)- R^7A, wherein R^7A is selected from C8-C18 alkyl and C8-C18 alkenyl having one C-C double bond. In a preferred embodiment the compound of formula (b1-b) has the structure shown in formula (b-V):

The lipidoid according to formula (b-V) or (b-VI) may be prepared as described e.g., in WO 2016075154 A1, EP 3013964 B1, and Jarzębińska et al., (Angew. Chem. Int. Ed.2016, 55, 9591). The ionizable lipidoid can be prepared by mixing N1-(2-aminoethyl)-N3-(2-((3,4- dimethoxybenzyl)amino)ethyl)propane-1,3-diamine (8.9 g, 1 eq., 28.67 mmol) with 1,2- Epoxydodecane (42.27, 8 eq., 229.4 mmol) and mixed for 24 h at 80 °C under constant shaking followed by purification and removal of the 3,4-dimethoxybenzyl protection group. Different isomers, of the lipidoid according to formula (b-V) can be used such as a racemate, an S-isomer, and/or an R-isomer. Preferably, the lipidoid according to formula (V) is used as pure R- isomer and has the structure shown in formula (b-VI). For obtaining pure R-isomers of the lipidoid according to formula (b-VI), it can be prepared as described above for the lipidoid of formular (b- V) using the R-isomer of 1,2-epoxydodecane for synthesis. Hence, in a preferred embodiment the pharmaceutical composition comprises an mRNA encoding GM-CSF, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, and a lipidoid having the structure shown in formula (b-V), preferably as shown in formula (b-VI). In certain embodiments the pharmaceutical composition comprises an mRNA molecule encoding

GM-CSF and a lipidoid having the structure shown in formula (b-V), preferably as shown in formula (b-VI). Optionally the pharmaceutical composition further comprises an mRNA molecule encoding IFNλ or IFNγ. A further preferred lipidoid is an ionizable lipidoid according to formula (b-VII). Hence, in further preferred embodiments the pharmaceutical composition comprises an mRNA molecule encoding GM-CSF, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, and further comprises a lipidoid having the structure shown in formula (b-VII).

In preferred embodiments the pharmaceutical composition further comprises an mRNA encoding GM-CSF and further comprises a lipidoid having the structure shown in formula (b-VII). Optionally the pharmaceutical composition further comprises an mRNA molecule encoding IFNλ or IFNγ. As component (c), the pharmaceutical composition may comprise ionizable lipidoids helper lipids as described in the following. In particular, the herein described agents and reagents for delivering and/or introducing the RNA into a target cell or a target tissue and the herein described lipids and lipidoids may be combined with one or more (e.g., two, three or four) further lipid(s) (like, for example, cholesterol, DPPC, DOPE and/or PEG-lipids (e.g. DMPE-PEG, DMG-PEG2000)). These further lipids may support the desired function of the agents/reagents and LTRs (support and/or increase the delivery and/or introduction of RNA into the cell or tissue and improve transfection efficiency, respectively) and function as respective “helper lipids”. Particular examples of such “helper lipids” are cholesterol, DPPC, DOPE and/or PEG-lipids (e.g., DMPE- PEG, DMG-PEG (e.g., DMG-PEG2000). The further lipids (e.g., “helper lipids”) may also be part(s) of the herein disclosed complexes/particles. The skilled person is readily in the position to prepare complexes/particles in accordance with the invention. Examples of further lipids (e.g., “helper lipids”) are also known in the art. The skilled person is readily in the position to choose suitable further lipids (e.g., “helper lipids”) and ratios of the agents/reagents/LTRs and the further lipids (e.g. “helper lipids”). Such ratios may be molar ratios of [1-4 : 1-5], [3-4 : 4-6], [about 4 : about 5], [about 4 : about 5.3] of agents/reagents/ LTRs : further lipid(s), (the more narrow ranges are preferred). For example, the agents/reagents/LTRs may be combined with three further lipids, like DPPC, cholesterol, and DMG-PEG2000, at a molar ration of (4-10):(4-7):(3-6):(0.3-3), preferably (6-9):(4-7):(3-6):(0.3-3), more preferably 8:(4-7):(3-6):(0.3-3), preferably at a molar ratio of about 8 (e.g. about 8.0) : about 5 (e.g. about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), respectively, or, more particularly, about 8.00 : about 5.29 : about 4.41 : about 0.88, respectively. Preferably, the lipidoids according to formula (b-V), (b-VI) and (b-VII) are generated as described above and used with helper lipids DPPC and cholesterol and PEG-lipid DMG- PEG2000 at the molar ratios of (4-10):(4-7):(3-6):(0.3-3), preferably (6-9):(4-7):(3-6):(0.3-3), more preferably 8:(4-7):(3-6):(0.3-3), even more preferably about 8 (e.g. about 8.0) : about 5 (e.g. about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8.00:5.29:4.41:0.88, respectively, for formulating lipoid particles. Optionally, the final lipidoid/nucleic acid nitrogen/phosphate (N/P) ratio, standing for molar ratio of the nitrogen atoms of the lipidoid to one phosphate group of nucleic acid, is preferably 4 to 44, preferably 4 to 16, more preferably 8 nitrogen atoms of lipidoid per one phosphate group of the nucleic acid. Preferably the nucleic acid is an mRNA. More preferably the mRNA encodes a functional GM-CSF, more preferably a GM-CSF of SEQ ID NO:2. A composition in which the lipidoid of Formula (b-VI) is formulated with the lipids DPPC, cholesterol and PEG-lipid DMG-PEG2000 at the molar ratios 8:5.29:4.41:0.88 is also referred herein as “Formulation I”. A composition in which the lipidoid of formula (b-VII) is formulated with the lipids DPPC and cholesterol and PEG-lipid DMG-PEG2000 at the molar ratios 8:5.29:4.41:0.88 is also referred herein as “Formulation II”. As also exemplarily described e.g. in WO 2016/075154 A1, EP 3013964 B1, and Zhang et al. (TERMIS, 2019, Tissue Engineering: Part A, Vol.25, Numbers 1 and 2), the lipidoids according to formula (b-V), (b-VI) and (b-VII) can be used as a non-viral vector, to make a stable lipoplex with mRNA molecules, based on electrostatic interaction between the ionizable amino groups of the lipidoids and negatively charged phosphate groups of mRNA molecules (Anderson, Human Gene Therapy 14, 2003, 191-202). To stabilize the lipoplex structure the lipidoids according to formula (b-V), (b-VI) or (b-VII), can be supplied with helper lipids, such as 1,2-dipalmitoyl-sn- glycero-3-phosphocholine (DPPC) and cholesterol (Anderson, Drug Delivery 11, 2004, 33-39; Liang, Journal of Colliod and Interface Science 278, 2004, 53-62) and 1,2-Dimyristoyl-sn-glycerol, methoxypolyethylene Glycol (DMG-PEG) 2kD (DMG-PEG2000) to provide a PEGylated liposome or lipid particle. It is well known that PEGylation improves the physico-chemical characteristics of liposomes / LNP / LiNP formulation by increasing suspensability in water, protecting from aggregation and from enzymatic degradation, and limiting immunogenic and antigenic reactions (Milla, Current Drug Metabolism 13, 2012, 105-119). Preferably, the molar ratio of lipidoid according to formula (b-V), (b-VI) or (b-VII) to nucleic acid is defined by the nitrogen/phosphate (N/P) ratio, i.e. the molar ratio of the nitrogen atoms of the lipidoid according to formula (b-V), (b- VI) or (b-VII)) to the phosphate groups of a nucleic acid molecule and is preferably 4 to 44, more preferably 4 to 16, and most preferably 8. In accordance with a further exemplary embodiment, component (b) comprises or consists of an ionizable lipid of formula (b-2)

wherein R^1B is an organic group comprising one or more primary, secondary or tertiary amino groups, or a protonated form thereof, wherein one or more of the nitrogen atoms contained in the primary, secondary or tertiary amino groups comprised by R^1B are protonated to provide a compound carrying a positive charge. Preferably, the compound of formula (b-2) has the following structure (b-2a):

In accordance with another exemplary embodiment, component (b) comprises or consists of an ionizable lipid of formula (b-3)

wherein R^1C and R^2C are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, R^3C is a C1-C6 alkanediyl group, preferably a C2 or C3 alkanediyl group, and R^4C and R^5C are independently hydrogen or C1-C3 alkyl, and are preferably methyl; or a protonated form thereof, wherein one or more of the nitrogen atoms contained in the compound of formula (b-3) are protonated to provide a compound carrying a positive charge. As an example of an ionizable lipid of formula (b-3), reference can be made to DLin-MC3-DMA (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino)butanoate). In accordance with still another exemplary embodiment, component (b) comprises or consists of an ionizable lipid of formula (b-4)

wherein R^1D and R^2D are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, R^3D is a C1-C6 alkanediyl group, preferably a C2 alkanediyl groupy, and R^4D and R^5D are independently hydrogen or C1-C3 alkyl, and are preferably methyl; or a protonated form thereof, wherein one or more of the nitrogen atoms contained in the compound of formula (b-4) are protonated to provide a compound carrying a positive charge. In accordance with still another exemplary embodiment, component (b) comprises or consists of an ionizable lipidoid of formula (b-5)

wherein R^1E to R^5E are independently of each other selected from hydrogen, -CH2-CH(OH)-R^7E, -CH(R^7E)-CH2-OH, -CH2-CH2-(C=O)-O-R^7E, -CH2-CH2-(C=O)-NH-R^7E and -CH2-R^7E wherein R^7E is selected from C3-C18 alkyl or C3-C18 alkenyl having one C-C double bond, provided that at least two residues among R^1E to R^5E are selected from -CH₂-CH(OH)-R^7E, -CH(R^7E)-CH₂-OH, - CH₂-CH₂-(C=O)-O-R^7E, -CH₂-CH₂-(C=O)-NH-R^7E and -CH₂-R^7E wherein R^7E is selected from C3-C18 alkyl or C3-C18 alkenyl having one C-C double bond; or a protonated form thereof, wherein one or more of the nitrogen atoms contained in the compound of formula (b-5) are protonated to provide a compound carrying a positive charge. In formula (b-5), R^1E to R^5E are preferably independently -CH₂-CH(OH)-R^7E, wherein R^7E is selected from C8-C18 alkyl or C8-C18 alkenyl having one C-C double bond. Still another exemplary ionizable lipid suitable for use in the present invention which may be comprised in component (b) or of which component (b) may consist is the ionizable lipid disclosed as “cationic lipid of Formula I” in the PCT application WO 2012/000104 A1, starting on page 104 of this document, and including all specific embodiments thereof also discussed in this document. Further exemplary ionizable lipidoids suitable for use in the present invention which may be comprised in component (b) or of which component (b) may consist are the ionizable lipidoids disclosed and claimed as “aminoalcohol lipidoids” in the PCT application WO 2010/053572 A2, including the compounds of all of the general formulae shown in the summary of the invention on page 4 of the document, and further defined in the remaining application. Still further exemplary ionizable lipidoids suitable for use in the present invention which may be comprised in component (b) or of which component (b) may consist are the ionizable lipidoids disclosed as amine containing lipidoids of formulae I to V in the PCT application WO 2014/028487 A1, including specific embodiments thereof. As preferred optional components in addition to the nucleic acid and the ionizable lipid or the ionizable lipidoid, the nanoparticles in the aqueous suspension formulation and in the aerosol of the present invention may comprise one or more of the following components (c1) to (c6): (c1) a non-ionizable lipid having a sterol structure; (c2) a phosphoglyceride lipid; (c3) a PEG-conjugated lipid; (c4) a polysarcosine-conjugated lipid; (c4) a PASylated lipid; and/or (c5) a cationic polymer. Component (c1) is a lipid having a sterol structure. As such, suitable lipids are compounds which have a steroid core structure with a hydroxyl group at the 3-position of the A-ring. An exemplary non-ionizable lipid having a sterol structure which may be comprised by component (c1) or of which component (c1) may consist has a structure of formula (c1-1)

wherein R^1K is a C3-C12 alkyl group. Further exemplary non-ionizable lipids having a sterol structure which may be comprised by component (c1) or of which component (c1) may consist include those disclosed by S. Patel et al., Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA, Nature Communications, 2020, 11:983, in particular those illustrated in Fig.2 of the publication. Preferably, component (c1) comprises or consists of cholesterol. Component (c2) is a phosphoglyceride. Preferably, component (c2) comprises or consists of a phospholipid selected from a compound of formula (c2-1) wherein R^1F and R^2F are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, or a pharmaceutically acceptable salt thereof; and a phospholipid of formula (c2-2)

wherein R^1G and R^2G are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, or a pharmaceutically acceptable salt thereof. More preferably, component (c2) comprises or consists of 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC) or a pharmaceutically acceptable salt thereof. Exemplary salt forms of the compound of formula (c2-1) include salts formed by the acidic –OH group with a base, or salts formed by the amino group with an acid. As salts formed with a base, mention may be made of alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts and ammonium salts. As exemplary salts formed with an acid, mention may be made of a salt formed with the acidic groups of the nucleic acid, but other salts are not excluded, and mineral acid salts such as chloride, bromide, or iodide, sulfate salts, nitrate salts, phosphate salts, hydrogenphosphate salts, or dihydrogenphosphate salts, carbonate salts, and hydrogencarbonate salts may be mentioned as examples. Exemplary salt forms of the compound of formula (c2-2) include salts formed by the acidic –OH group attached to the P atom with a base, or salts formed by the quaternary amino group with an anion. As salts formed with a base, mention may be made of alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts and ammonium salts. As exemplary salts formed with anion, mention may be made of a salt formed with the acidic groups of the nucleic acid, but other salts are not excluded, and mineral acid salts such as chloride, bromide, or iodide, sulfate salts, nitrate salts, phosphate salts, hydrogenphosphate salts, or dihydrogenphosphate salts, carbonate salts, and hydrogencarbonate salts may be mentioned as examples. Component (c3) is a PEG-conjugated lipid, i.e. a lipid which is covalently linked with a polyethylene glycol chain. Preferably, component (c3) comprises or consists of a PEG-conjugated lipid selected from a compound of formula (c3-1)

wherein R^1H and R^2H are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, and p is an integer of 5 to 200, preferably 10 to 100, and more preferably 20 to 60; and a compound of formula (c3-2) wherein R^1J and R^2J are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, and q is an integer of 5 to 200, preferably 10 to 100, and more preferably 20 to 60 or a pharmaceutically acceptable salt thereof. Exemplary salt forms of the compound of formula (c3-2) include salts formed by the acidic –OH group attached to the P atom with a base. As salts formed with a base, mention may be made of alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts and ammonium salts. More preferably, component (c3) comprises or consists of 1,2-dimyristoyl-sn- glycerolmethoxy(polyethylene glycol) (DMG-PEG), and still more preferably component d) comprises or consists of 1,2-dimyristoyl-sn-glycerolmethoxy(polyethylene glycol)-2000 (DMG- PEG2k). Component (c4) is a polysarcosine-conjugated lipid, i.e. a lipid which is covalently linked with a polymeric moiety of the formula (c4-1): -[C(O)-CH2-N(CH3)]r- (c4-1) wherein r denotes the number of repeating units, and is preferably 10 to 100. Component (c5) is a PASylated lipid, i.e. a lipid which is covalently linked with a polymeric moiety formed by proline (pro)/alanine (ala)/serine (ser) repetitive residues. Component (c6) is a cationic polymer. Such polymers suitable for use in the formation of nanoparticles comprising a nucleic acid are known in the art. Exemplary suitable cationic polymers are discussed in A.C. Silva et al., Current Drug Metabolism, 16, 2015, 3-16, and in the literature referred to therein, in J.C. Kasper et al., J. Contr. Rel. 151 (2011), 246-255, in WO 2014/207231 and in the literature referred to therein, and in WO 2016/097377 and in the literature referred to therein. Suitable cationic oligomers or polymers include in particular cationic polymers comprising a plurality of units wherein an amino group is contained. The amino groups may be protonated to provide the cationic charge of the polymer. Polymers are preferred which comprise a plurality of units independently selected from the following (1), (2), (3) and (4):

, wherein one or more of the nitrogen atoms of the repeating units (1), (2), (3) and/or (4) may be protonated to provide the cationic charge of the polymer. Particularly preferred as cationic polymers are the following four classes of polymers comprising a plurality of units wherein an amino group is contained. As the first preferred class, poly(ethylene imine) (“PEI”) is mentioned, including branched poly(ethylene imine) (“brPEI”). The second preferred class of cationic polymers are polymers comprising a plurality of groups of the following formula (c6-1) as a side chain and/or as a terminal group, as they are disclosed as groups of formula (II) in WO 2014/207231:

wherein the variables a, b, p, m, n and R² to R⁶ are defined as follows, independently for each group of formula (c6-1) in a plurality of such groups: a is 1 and b is an integer of 2 to 4; or a is an integer of 2 to 4 and b is 1, p is 1 or 2, m is 1 or 2; n is 0 or 1 and m+n is ≥ 2; and R² to R⁵ are, independently of each other, selected from hydrogen; a group -CH₂-CH(OH)-R⁷,-CH(R⁷)-CH₂-OH, -CH₂-CH₂-(C=O)-O-R⁷, -CH₂-CH₂-(C=O)-NH-R⁷ or -CH₂-R⁷ wherein R⁷ is selected from C3-C18 alkyl or C3-C18 alkenyl having one C-C double bond; a protecting group for an amino group; and a poly(ethylene glycol) chain; R⁶ is selected from hydrogen; a group -CH₂-CH(OH)-R⁷, -CH(R⁷)-CH-OH, -CH₂-CH₂-(C=O)- O-R⁷, -CH₂-CH₂-(C=O)-NH-R⁷ or -CH₂-R⁷ wherein R⁷ is selected from C3-C18 alkyl or C3- C18 alkenyl having one C-C double bond; a protecting group for an amino group; –C(NH)- NH₂; a poly(ethylene glycol) chain; and a receptor ligand, and wherein one or more of the nitrogen atoms indicated in formula (c6-1) may be protonated to provide a cationic group of formula (c6-1). As regards further preferred definitions of these polymers, and of the variables contained in formula (c6-1) above, the respective disclosure in WO 2014/207231 with regard to its groups of formula (II) also applies for the invention described herein. The third preferred class of cationic polymers are polymers comprising a plurality of groups of the following formula (c6-2) as repeating units, as they are disclosed as groups of formula (III) in WO 2014/207231:

wherein the variables a, b, p, m, n and R² to R⁵ are defined as follows, independently for each group of formula (c6-2) in a plurality of such groups: a is 1 and b is an integer of 2 to 4; or a is an integer of 2 to 4 and b is 1, p is 1 or 2, m is 1 or 2; n is 0 or 1 and m+n is ≥ 2; and R² to R⁵ are, independently of each other, selected from hydrogen; a group –CH₂-CH(OH)-R⁷, -CH(R⁷)-CH₂-OH, -CH₂-CH₂-(C=O)-O-R⁷, -CH₂-CH₂-(C=O)-NH-R⁷ or - CH₂-R⁷, wherein R⁷ is selected from C3-C18 alkyl or C3-C18 alkenyl having one C-C double bond; a protecting group for an amino group; –C(NH)-NH₂; and a poly(ethylene glycol) chain; and wherein one or more of the nitrogen atoms indicated in formula (c6-2) may be protonated to provide a cationic group of formula (c6-2). As regards further preferred definitions of these polymers, and of the variables contained in formula (c6-2) above, the respective disclosure in WO 2014/207231 with regard to its repeating units of formula (III) also applies for the invention described herein. The fourth preferred class of cationic polymers is provided by a statistical copolymer as it is disclosed in WO 2016/097377. It comprises a plurality of repeating units (a) independently selected from repeating units of the following formulae (a1) and (a2):

and a plurality of repeating units (b) independently selected from repeating units of the following formulae (b1) to (b4):

and the molar ratio of the sum of the repeating units (a) to the sum of the repeating units (b) lies within the range of 0.7/1.0 to 1.0/0.7, and one or more of the nitrogen atoms of the repeating units (a) and/or (b) contained in the copolymer may be protonated to provide a cationic copolymer. As regards further preferred definitions of this copolymer, the respective disclosure in WO 2016/097377 also applies for the invention described herein. As noted therein, a particularly preferred copolymer is a linear copolymer which comprises repeating units (a1) and (b1), or which consists of repeating units (a1) and (b1). As an optional component of the nanoparticles, a polyanion component which is different from the nucleic acid may also be comprised. Examples of such a polyanion are polyglutamic acid and chondroitin sulfate. If such a polyanion component different from the nucleic acid is used in the nanoparticles, its amount is preferably limited such that the amount of anionic charges provided by the polyanion component is not higher than the amount of the anionic charges provided by the nucleic acid. As explained above, the lipid or lipidoid nanoparticles which may be present in the pharmaceutical composition and/or in an aerosol in accordance with the invention comprise (a) a nucleic acid and (b) an ionizable lipid or an ionizable lipidoid. If a lipidoid is comprised, the nanoparticles shall be referred to herein as lipidoid nanoparticles. Preferably, the nanoparticles comprise, more preferably consist of, the nucleic acid (a), the ionizable lipid or ionizable lipidoid (b), and optionally one or more of the non-ionizable lipid having a sterol structure (c1); the phosphoglyceride lipid (c2); the PEG-conjugated lipid (c3); the polysarcosine-conjugated lipid (c4); the PASylated lipid (c5); and the cationic polymer (c6). Exemplary suspension formulations comprising nanoparticles formed from the components listed above, which are also suitable for use in the context of the present invention, include those disclosed by S. Patel et al., Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA, Nature Communications, 2020, 11:983. It will be understood that components of the nanoparticles, and in particular components (a) and (b), and optionally one or more of (c1) to (c6), are typically contained as a mixture in the nanoparticles. In terms of the amounts of these components, it is further preferred that the nanoparticles comprise, more preferably consist of: the nucleic acid, and 30 to 65 mol% of the ionizable lipid or ionizable lipidoid (b), and one or more of the following components: 10 to 50 mol% of the lipid having a sterol structure (c1), 4 to 50 mol% of the phosphoglyceride lipid (c2), 0.5 to 10 mol% of one of the PEG-conjugated lipid (c3), the polysarcosine-conjugated lipid (c4) and the PASylated lipid (c5), or of any combination thereof, 0.5 to 10 mol% of the cationic polymer (c6), such that the sum of (b) and (c1) to (c6) amounts to 100 mol%. As will be understood, the molar percentages for components (c1) to (c6) are indicated with the proviso that not all of these components need to be present in the nanoparticles. Thus, for example, the cationic polymer can be present or absent in the context of this preferred embodiment, but if it is present, it is used in the amount of 0.5 to 10 mol%. As further indicated above, the amount of component(s) (c1), (c2), (c3), (c4), (c5) and/or (c6) in the context of this preferred embodiment is such that the sum of (b) and (c1) to (c6) amounts to 100 mol%. It is still further preferred that the nanoparticles comprise, or consist of: the nucleic acid (a), the ionizable lipid or ionizable lipidoid (b), the non-ionizable lipid having a sterol structure (c1), the phosphoglyceride lipid (c2), and/or the PEG-conjugated lipid (c3). In terms of the amounts of these components, it is still further preferred that the nanoparticles comprise, more preferably consist of the nucleic acid (a), 30 to 65 mol% of the ionizable lipid or ionizable lipidoid (b), 10 to 50 mol% of the lipid having a sterol structure (c1), 4 to 50 mol% of the phosphoglyceride lipid (c2), and/or 0.5 to 10 mol% of the PEG-conjugated lipid (c3), such that the sum of (b) and (c1) to (c3) amounts to 100 mol%. In line with the above information related to preferred nucleic acids and related to the preferred components of the lipid composition other than the nucleic acid, the lipid nanoparticles contained in the suspension formulation in accordance with the invention and in the aerosol in accordance with the invention, respectively, preferably comprise (a) mRNA as a nucleic acid; (b) an ionizable lipidoid of formula (b-1b)

wherein R^1A to R^6A are independently selected from hydrogen and -CH2-CH(OH)-R^7A, wherein R^7A is selected from C8-C18 alkyl and C8-C18 alkenyl having one C-C double bond, provided that at least two residues among R^1A to R^6A are -CH₂-CH(OH)-R^7A, more preferably at least four residues among R^1A to R^6A are -CH₂-CH(OH)-R^7A, wherein R^7A is selected from C8-C18 alkyl and C8-C18 alkenyl having one C-C double bond; or a protonated form thereof wherein one or more of the nitrogen atoms indicated in formula (b- 1b) are protonated to provide a cationic lipidoid; (c1) a non-ionizable lipid having a sterol structure of formula (c1-1) wherein R^1K is a C3-C12 alkyl group; (c2) a phosphoglyceride of formula (c2-2)

wherein R^1G and R^2G are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, or a pharmaceutically acceptable salt thereof; and (c3) a PEG conjugated lipid of formula (c3-1)

wherein R^1H and R^2H are independently selected from a C8-C18 alkyl group and a C8-C18 alkenyl group, preferably from a C12-C18 alkyl group and a C12-C18 alkenyl group, and p is an integer of 5 to 200, preferably 10 to 100, and more preferably 20 to 60. In the nanoparticles contained in the suspension formulation and in the aerosol in accordance with the invention, the composition of the nanoparticles is preferably such that the weight ratio in the nanoparticles of the sum of the weights of components other than the nucleic acid to the weight of the nucleic acid is in the range of 30:1 to 1:1, more preferably 20:1 to 2:1 and most preferably 15:1 to 3:1. The N/P ratio, i.e. the ratio of the number of amine nitrogen atoms provided by the ionizable lipid or the ionizable lipidoid to the number of phosphate groups provided by the nucleic acid of the nanoparticles is preferably in the range of 0.5 to 20, more preferably in the range of 0.5 to 10. The lipid or lipidoid nanoparticles contained in the suspension formulation and in the aerosol in accordance with the invention preferably have a Z-average diameter in the range of 10 to 500 nm, more preferably in the range of 10 to 250 nm, still more preferably 20 to 200 nm. The indicated particle diameter is the hydrodynamic diameter of the particles, as determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C. The polydispersity index of the nanoparticles contained in the suspension formulation and in the aerosol in accordance with the invention is preferably in the range of 0.05 to 0.4, more preferably in the range of 0.05 to 0.2. The polydispersity index can be determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C It is possible to provide a suspension formulation or an aerosol containing different lipid or lipidoid nanoparticles as defined above, i.e. particles which differ in terms of their components. However, preferably the nanoparticles contained in the suspension formulation in accordance with the invention or in the aerosol in accordance with the invention are composed of the same components. The lipid nanoparticles can be conveniently prepared by mixing a solution containing the nucleic acid, e.g. in an aqueous solvent containing a buffer, such as a citrate buffer with a pH of 4.5, and optionally containing a salt such as sodium chloride, and a solution containing the ionizable lipid or ionizable lipidoid, e.g. in ethanol. Further optional components can be incorporated e.g. by adding them to one of the two solutions. The lipid nanoparticles generated in this manner can be further processed by chromatography and/or dialysis and/or tangential flow filtration in order to obtain the lipid nanoparticles in a desired liquid composition. Before or during these downstream processing steps, further excipients such as cryoprotectants and other excipients can be added to obtain a desired pharmaceutical composition. If the nanoparticles are subjected to tangential flow filtration, it is preferred for stability reasons to carry out the filtration on a suspension of the nanoparticles comprising the triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks as defined as a component of the vehicle solution herein. To that extent, the invention further provides a method for the preparation of the aqueous suspension formulation for aerosol formation comprising lipid or lipidoid nanoparticles which are suspended in an aqueous vehicle solution, said method comprising a step of mixing a solution containing the nucleic acid (a), and a solution containing the ionizable lipid or ionizable lipidoid (b), to form a suspension comprising the lipid or lipidoid nanoparticles. Further components, such as one or more of components (c1) to (c6) can be conveniently incorporated into the nanoparticles e.g. by adding them to the solution containing the ionizable lipid or the ionizable lipidoid. As a preferred embodiment, the invention provides a method for the preparation of the aqueous suspension formulation for aerosol formation comprising lipid or lipidoid nanoparticles which are suspended in an aqueous vehicle solution, said method comprising a step of mixing a solution containing the nucleic acid (a), and a solution containing the ionizable lipid or ionizable lipidoid (b), to form a suspension comprising the lipid or lipidoid nanoparticles; a step of adding the triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks as defined herein to the suspension; and a step of subjecting the suspension to tangential flow filtration to yield the aqueous suspension formulation in accordance with the invention. The aqueous suspension formulation for aerosol formation comprises the lipid or lipidoid nanoparticles discussed above together with an aqueous vehicle solution. As indicated by the reference to a suspension formulation, the nanoparticles are suspended in the vehicle solution. The vehicle solution is an aqueous solution, i.e. a solution wherein the main solvent, in terms of the total volume of solvent(s), is water, preferably a solution containing more than 70 % of water, more preferably more than 90 % of water, as a solvent, indicated as the volume percentage of water in the total volume of solvent(s) contained in the vehicle solution (at a temperature of 25 °C). Most preferably, water is the only solvent in the vehicle solution. Thus, the vehicle solution is a liquid at room temperature (e.g.25 °C). The weight per volume ratio of the nanoparticles in the vehicle solution in the composition is preferably in the range 0.5 g/L to 100 g/L, preferably 10 g/L to 100 g/L, more preferably 10 g/L to 50 g/L and most preferably 10 g/L to 75 g/L. The concentration of the nucleic acid, provided by the lipid or lipidoid nanoparticles, in the suspension formulation preferably ranges from 0.01 to 10 mg/ml, more preferably from 0.02 to 5 mg/ml, and most preferably from 0.1 to 5 mg/ml, based on the total volume of the suspension formulation. As noted above, the lipid or lipidoid nanoparticles contained in the suspension formulation and in the aerosol in accordance with the invention preferably have a Z-average diameter in the range of 10 to 500 nm, more preferably in the range of 10 to 250 nm, still more preferably 20 to 200 nm. The indicated particle diameter is the hydrodynamic diameter of the particles, as determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C. The polydispersity index of the nanoparticles contained in the suspension formulation and in the aerosol in accordance with the invention is preferably in the range of 0.05 to 0.4, more preferably in the range of 0.05 to 0.2. The polydispersity index can be determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C The vehicle solution may comprise a triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks. Preferably, the triblock copolymer is an A-B-A triblock copolymer which contains one poly(propylene oxide) block B of formula (p-1):

wherein s is an integer of 15 to 67, preferably 20 to 40, and two poly(ethylene oxides) blocks A of formula (p-2):

_(p-2) wherein r is, independently for each block, an integer of 2 to 130, preferably 50 to 100, and more preferably 60 to 90. More preferably, the triblock copolymer has the following structure:

wherein r and t are independently of each other integers of 2 to 130, preferably 50 to 100, and more preferably 60 to 90, and s is an integer of 15 to 67, preferably 20 to 40. Most preferably, Poloxamer P188 is used as the triblock copolymer. The vehicle solution may comprises the triblock copolymer dissolved therein. However, as will be appreciated by the skilled reader, this does not exclude the possibility that a certain amount of the copolymer molecules is adsorbed to the lipid or lipidoid nanoparticles which are contained in the composition. Preferably, the composition for aerosol formation comprises the triblock copolymer at a concentration of 0.05 to 5 % w/v (i.e. gram per 100 mL) preferably 0.1 to 2 %, based on the total volume of the composition. In addition to the triblock copolymer, other excipients may be present in the vehicle solution. Preferably, the vehicle solution further comprises at least one of sucrose and NaCl, more preferably sucrose and NaCl. The pharmaceutical formulation in accordance with the invention can be conveniently prepared e.g. by a method including adding the triblock copolymer to a suspension comprising a vehicle solution and the lipid or lipidoid nanoparticles, or including adding the lipid or lipidoid nanoparticles to a vehicle solution comprising the triblock copolymer. The aqueous suspension formulation for aerosol formation in accordance with the present invention can be nebulized to provide the aerosol in accordance with the invention. Advantageously, a negative influence of the nebulization step on the nanoparticles and the nucleic acid contained in the aqueous suspension formulation can be minimized or even avoided in this manner. Moreover, the nebulization can be accomplished in an efficient manner within a reasonable period of time of e.g.60 minutes or less, preferably 30 min or less, for a given dose of mRNA. Thus, the aerosol which is obtainable by nebulization of the aqueous suspension formulation for aerosol formation in accordance with the invention comprises aerosol droplets dispersed in a gas phase. The aerosol droplets comprise the lipid or lipidoid nanoparticles as discussed above, including any preferred embodiments thereof, and an aqueous vehicle solution for the nanoparticles. The aqueous vehicle solution comprises the triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks that is provided by the vehicle solution of the aqueous suspension formulation of the invention, and is discussed in this context above. The presence of the triblock copolymer allows the favorable nanoparticle characteristics to be retained which are exhibited by the nanoparticles of the aqueous suspension formulation discussed above prior to nebulization. Thus, the lipid or lipidoid nanoparticles contained in the aerosol droplets of the aerosol in accordance with the invention preferably have a Z-average diameter in the range of 10 to 500 nm, more preferably in the range of 10 to 250 nm, still more preferably 20 to 200 nm. The indicated particle diameter is the hydrodynamic diameter of the particles, as determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C. The polydispersity index of the lipid or lipidoid nanoparticles contained in the aerosol droplets of the aerosol in accordance with the invention is preferably in the range of 0.05 to 0.4, more preferably in the range of 0.05 to 0.2. The polydispersity index can be determined by dynamic light scattering (DLS). Measurements are generally carried out at 25 °C. The vehicle solution in the aerosol droplets of the aerosol which is derived from the suspension formulation is an aqueous solution, i.e. a solution wherein the main solvent, in terms of the total volume of solvent(s), is water. Preferably, the vehicle solution contains more than 70 % of water, more preferably more than 90 % of water, as a solvent, indicated as the volume percentage of water in the total volume of solvent(s) contained in the vehicle solution (at a temperature of 25 °C). Most preferably, water is the only solvent in the vehicle solution. As noted above, the aerosol in accordance with the invention comprises droplets dispersed in a gas phase, typically dispersed in air. The droplets are obtainable via the nebulization of the composition for aerosol formation in accordance with the invention. They comprise a liquid phase which is derived from the vehicle solution of the composition described in detail above, and the lipid or lipidoid nanoparticles. Typically, the lipid or lipidoid nanoparticles are dispersed in the vehicle solution. Moreover, the aerosol droplets typically comprise a plurality of the lipid or lipidoid nanoparticles dispersed in a single droplet. As further explained above, the aerosol in accordance with the invention can be administered to a subject, in particular to or via the respiratory tract of the subject, preferably via pulmonary administration or nasal administration. Typically, the administration is accomplished via inhalation of the aerosol by the subject. Aerosol droplets can be characterized via their aerodynamic diameter, which takes into account their density and their shape. The aerodynamic diameter is defined as the diameter of a spherical particle or droplet with a density of 1 g/cm³, which has the same sinking speed in air as the droplet under consideration (Luftbeschaffenheit - Festlegung von Partikelgrößenverteilungen für die gesundheitsbezogene Schwebstaubprobenahme, (1995); Vincent JH. Aerosol Sampling - Science, Standards, Instrumentation and Applications. Chichester, England: John Wiley & Sons, Ltd.; 2007). Size distributions of the aerodynamic diameter are often parameterized via the Mass Median Aerodynamic Diameter (MMAD), i.e. the median mass-related aerodynamic diameter. The MMAD is thus the diameter at which particles smaller or larger than this value each contribute 50% of the total mass and thus a measure of the average size of a particle. The MMAD can be measured with a cascade impactor or a next generation impactor (Preparations for inhalation: Aerodynamic assessment of fine particles; European Pharmacopoeia 90; Volume I: EDQM Council of Europe; 2019). The mass median aerodynamic diameter (MMAD) of an aerosol droplet has an impact on where in the respiratory tract an aerosol particle will deposit. While particles with an MMAD of 10 μm or more tend to be already deposited (impacted) at the throat due to their inertia, particles between 0.1 μm and 1.0 μm tend to be too light and may be exhaled again due to diffusion processes caused by Brownian motion. The aerosol droplets of the aerosol in accordance with the invention preferably have an MMAD, as determined by measurement using a cascade impactor or a next generation impactor of 2 to 10 µm, more preferably 3 to 8 µm. In some embodiments, the pharmaceutical composition comprises the nucleic acid is in the form of a lipid nanoparticle (LNP) or a lipidoid nanoparticle formulation (LiNP). In preferred embodiments, the pharmaceutical composition comprises an mRNA in the form of a lipidoid nanoparticle (LiNP) formulation. In an embodiment, the pharmaceutical composition according to the invention comprises an LiNP nanoparticle formulation comprising a nucleic acid, preferably mRNA and : a) a lipidoid according to formula (b-1), (b-1b), (b-V), (b-VI), and/or (b-VII), and b) one or more helper lipid(s), optionally selected from: b1) 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and/or b2) cholesterol, and/or b3) PEG-lipid DMG-PEG2000. In preferred embodiments, a lipidoid is according to formula (b-1b). In more preferred embodiments, the pharmaceutical composition comprises the R isomer of the lipidoid of formula (b-V) as shown in formula (b-VI). In preferred embodiments all four elements (lipidoid, DPPC, cholesterol, and PEG-lipid DMG-PEG2000) are present. At a molar ratio of (4-10):(4-7):(3-6):(0.3- 3), preferably (6-9):(4-7):(3-6):(0.3-3), more preferably 8:(4-7):(3-6):(0.3-3), even more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively. Optionally, the composition comprises a triblock copolymer as component (p) as disclosed herein. In some embodiments, the pharmaceutical composition comprises an LNP that comprises as component (a) a nucleic acid of the invention. In preferred embodiments the pharmaceutical composition comprises a nucleic acid, preferably an mRNA, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, encoding GM-CSF and further comprises a lipidoid as disclosed herein, preferably a lipidoid according to formula (b-V), (b-VI) or (b-VII)), optionally formulated with DPPC, cholesterol, and DMG-PEG2000.Moreover, in particularly preferred embodiments the pharmaceutical composition comprises an mRNA, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, encoding GM-CSF and further comprises a lipidoid according to formula (b-V), (b-VI) or (b-VII) formulated with DPPC, cholesterol, and DMG-PEG2000. In some embodiments, the molar ratio of the lipidoid according to formula (b-V), (b-VI) or (b-VII) / DPPC / cholesterol / DMG-PEG2000, respectively is (4-10):(4-7):(3-6):(0.3-3), preferably (6-9):(4-7):(3-6):(0.3-3), more preferably 8:(4- 7):(3-6):(0.3-3), even more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively. Preferably, the molar ratio of lipidoid and helper lipids is 8.00 (lipidoid) : 5.29 (DPPC) : 4.41 (cholesterol): 0.88 (DMG-PEG2000) respectively. For complexation with the nucleic acid, lipidoid and helper lipids are preferably provided in alcoholic, preferably ethanolic solution at said molar ratios while the nucleic acid is provided in aqueous solution preferably of acidic pH. The lipidoid an mRNA solutions can be mixed by pipetting or using a fine needle syringe. Preferably, the mixing is accomplished by automated mixing, for example using an instrument for microfluidic mixing or for mixing through at T-piece. Preferably, the volume ratio of alcoholic lipid mixture to aqueous solution of nucleic acid is 1:4. Preferably, the resulting formulation is further processed by dialysis or tangential flow filtration to remove the alcohol and to generate an aqueous suspension of lipidoid nanoparticles. Hence, in particularly preferred embodiments of the pharmaceutical composition comprising a nucleic acid, preferably an mRNA, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, encoding GM-CSF, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, said pharmaceutical composition further comprises a formulation generated as described above comprising a lipidoid according to formula (b-VI) or (b-VII). Dosages As shown in the appended Examples, experiments in mice show that an induction of downstream targets of GM-CSF (which is indicative of correct signaling induced by GM-CSF binding to its receptors) can already be achieved with extremely low doses of GM-CSF mRNA when administered via instillation into the lung. Further studies in mice shows that the administrated mRNA of the invention leads to a positive clinical benefit. When extrapolated to human patients based on the lung surface area, it can be expected that effective amounts of GM-CSF mRNA will lie in the range of 200 µg to 15 mg, per dose, preferably between 250 µg and 5 mg per dose, even more preferably 250 µg and 1 mg per dose, even more preferably between 250 µg and 750 µg per dose. In some embodiments the patient receives 6.3 mg, 2.8 mg or 1.4 mg per dose. However, the nucleic acids and pharmaceutical composition of the invention may be administered to a subject as determined by a physician or in dose finding clinical studies. In some embodiments the pharmaceutical composition of the invention is administered, once a day, b.i.d or t.i.d; In some embodiments the nucleic acid and compositions of the invention are administered less frequently than once a day, such as once every 36 hours, once every 48 hours or once a week. In some embodiments, the pharmaceutical composition or nucleic acid of the present invention is administered once to three times a week. In preferred embodiments the composition is administered twice a week. In some embodiments, the pharmaceutical composition or nucleic acid of the present invention is administered preferably two or three times a week, for at least 1 week, preferably for at least 2 weeks, more preferably for at least 3 weeks and even more preferably for at least 4 weeks. Preferably, the pharmaceutical composition is administered twice a week for at least 4 weeks. In some embodiments, the pharmaceutical composition or nucleic acid of the present invention when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of about 200 µg to about 15 mg. In some embodiments, the pharmaceutical composition or nucleic acid of the present invention when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of preferably about 1 mg to about 10 mg in each treatment day. In some preferred embodiments, the pharmaceutical composition or nucleic acid of the present invention when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of about 4.5 mg of nucleic acid in each treatment day. Cells A further aspect of the invention relates to a cell comprising an exogenous modified nucleic acid coding for GM-CSF. In a further aspect, the invention provides a cell comprising a nucleic acid of the invention. In an embodiment, the modified nucleic acid is an exogenous modified mRNA. In an embodiment, the invention relates to a cell comprising an exogenous modified mRNA comprising a codon optimized ORF coding for human GM-CSF. In general, any of the nucleic acids disclosed herein can be comprised in a cell. When a nucleic acid, such as a modified nucleic acid or modified mRNA, is comprised in a cell, it may be modified as described herein. In particular, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the nucleic acid when being comprised in a cell. In an embodiment, the modified cell comprises a nucleic acid or nucleic acid molecule as described herein. In one embodiment, the modified cell comprises a vector as described herein, or a mRNA as described herein. In certain embodiments, the modified cell comprises an exogenous mRNA coding for GM-CSF. Preferably, the mRNA is a modified mRNA. More preferably, the mRNA is as defined above under “Nucleic acids”. In even more preferred embodiments, the cell comprises a mRNA having at least 94% identity to SEQ ID NO:1, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39. Most preferably, the cell comprises the modified mRNA of SEQ ID NO:1 or SEQ ID NO:7. In certain embodiments of the invention, the cell is a respiratory airway cell, a skin cell and/or an immune cell. In preferred embodiments, the respiratory airway cell is a proximal airway cell, a distal airway cell or an alveolar cell. In certain embodiments of the invention, the cell is a cell selected from the list consisting of an adventitial fibroblast; alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell; fibromyocyte, goblet cell; ionocyte; lipofibroblast, lymphatic cell, mesothelial cell; myofibroblast; mucous cell, neuroendocrine cell; pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. In preferred embodiments the cell is resident or a migrating immune cell and/or an alveolar cell. More preferably, the cell is selected from the list consisting of a resident macrophage, a granulocyte, a migrating monocyte, a goblet cell, a ciliate cell and/or combinations thereof. In more preferred embodiments, the cell is an alveolar macrophage, granulocyte, or a migrating monocyte. I In some embodiments the cell is a stem cell or a precursor cell, preferably a stem cell or a precursor cell of a macrophage. More preferably the precursor cell is a precursor cell of a migrating macrophage or an alveolar macrophage. Alveolar macrophages (AMs) are a type of immune cell found in the alveoli of the lungs. Ams are the primary immune cells responsible for protecting the alveoli from infection and other harmful substances. They are part of the mononuclear phagocyte system, which also includes dendritic cells and tissue macrophages. Like other macrophages, alveolar macrophages are able to phagocytose, or engulf and digest, foreign particles and microorganisms. They also secrete various immune molecules, such as cytokines and chemokines, which help to recruit other immune cells to the site of infection. Alveolar macrophages play a critical role in the immune defense of the lungs, and their function is essential for maintaining the health of the respiratory system. Dysfunction or impairment of alveolar macrophages has been associated with a number of respiratory disorders, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and PAP. Thus in a most preferred embodiment, the cell of the invention is an alveolar macrophage (AM). The alveolar macrophage can an isolated AM from a patient or a resident AM in a patient body. In certain embodiments, the cells are modified in vivo (i.e., in the patient’s tissue) with the nucleic acid of the invention or alternatively the cells are modified in vitro or ex vivo, by isolating them from the body and contacting them in vitro or ex vivo with the nucleic acids of the invention to express GM-CSF and thus obtaining modified cells. The modified cells can be expanded, activated, and delivered to the patient using known methods of cell expansion, activation and delivery known to the skilled person in CAR-T cell technology. In further embodiments, the modified cell is a skin cell, preferably a living cell of the epidermis or the dermis. More preferably, the cell is a skin macrophage (SM). SM play a key role in maintaining the integrity and function of the skin barrier. They help to remove dead skin cells and other debris, and also play a role in wound healing by releasing growth factors and other signaling molecules that stimulate the proliferation and differentiation of other cells. There are several different types of macrophages that can be found in the skin and can be modified with the nucleic acids of the invention, including resident macrophages, and recruited macrophages. Resident macrophages are a type of tissue-resident macrophage that are found in specific locations within the body, such as the skin or liver. Recruited macrophages, on the other hand, are macrophages that are recruited to the site of an infection or injury in response to specific signals. Thus, in certain embodiments, the modified cell of the invention is a resident or a recruited skin macrophage. Preferably, said modified cell is a resident skin macrophage or a skin dendritic cell. In certain embodiments the LNPs or LiNPs are administered through intradermal, subcutaneous, and intralymphatic routes. In certain embodiments, the LNPs or LiNPs are as defined herein. Therapy and Uses The present disclosure provides methods of treating, ameliorating, or preventing one or more conditions in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one of the nucleic acids according to the invention. In one aspect, the invention provides a nucleic acid, preferably a modified mRNA, encoding GM- CSF or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, for use as a medicament. In another aspect, the invention provides a nucleic acid, preferably a modified mRNA, encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient. A further aspect of the invention relates to the nucleic acid or vector or cell or pharmaceutical composition of the invention for use in therapy. A further aspect of the invention relates to the nucleic acid, or vector, or cell or pharmaceutical composition according to the invention for use as a medicament. Preferably said nucleic acid is an mRNA, more preferably a modified mRNA as described herein. When a nucleic acid, such as a modified nucleic acid or modified mRNA, is used in any of the treatments described herein, it may be modified as described herein. In particular, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the nucleic acid when used in any of the treatments provided herein or when comprised in a cell or a pharmaceutical composition. When used in any of the treatments provided herein, a nucleic acid may be a modified nucleic acid. In some embodiments the nucleic acid used in any of the treatments provided herein may be a modified nucleic acid comprising a combination of unmodified nucleosides and chemically modified nucleosides. In some embodiments, in the nucleic acid used in any of the treatments provided herein, the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1- methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5- iodo-citosine and combinations thereof. In some embodiments the nucleic acid used in any of the treatments provided herein comprises the chemically modified nucleosides 2-thiouridine and 5- methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2- thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine. In some embodiments the nucleic acid used in any of the treatments provided herein comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1- methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine. In some embodiments the nucleic acid used in any of the treatments provided herein comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5- Iodocytidine. In some embodiments the nucleic acid used in any of the treatments provided herein comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). In preferred embodiments, the GM-CSF deficiency, the GM-CSF related disease or the disease caused by a GM-CSF deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. In a preferred embodiment, the disease to be treated, such as the GM-CSF deficiency, the GM-CSF related disease or the disease caused by a GM-CSF deficiency, is PAP, preferably aPAP. In some embodiments, the disease to be treated is a PAP related to a defective or deficient GM-CSF production or a defective or deficient GM-CSF receptor function. In a preferred embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the viral infections, such as Influenza and COVID-19, are lung viral infections. Accordingly, the invention provides a nucleic acid, preferably a modified mRNA, encoding GM- CSF or a functional fragment thereof for use in a method for the treatment or prevention of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. The invention also provides a nucleic acid, a cell or a pharmaceutical composition for use in a method for the treatment or prevention of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. The nucleic acid or modified nucleic acid for use as a medicament or for use in a treatment or administered in a method of treatment as disclosed herein is preferably a low-immunogenic nucleic acid. The nucleic acid or modified nucleic acid being comprised in a cell or a pharmaceutical composition of the present invention for use as a medicament or for use in a treatment or administered in a method of treatment as disclosed herein is preferably a low-immunogenic nucleic acid. Accordingly, the invention provides a nucleic acid, preferably a modified mRNA, encoding GM- CSF or a functional fragment thereof for use in a method for the treatment or prevention of a GM- CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient, wherein the nucleic acid is a low immunogenic nucleic acid. The invention also provides a modified nucleic acid, preferably a modified mRNA, encoding GM- CSF or a functional fragment thereof for use in a method for the treatment or prevention of a GM- CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient, wherein the nucleic acid is a low immunogenic nucleic acid, and wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. The invention also provides a nucleic acid, preferably a modified mRNA, or a cell or a pharmaceutical composition of the present invention, for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM- CSF deficiency in a subject or patient, wherein the nucleic acid is a low immunogenic nucleic acid. The invention also provides a modified nucleic acid, preferably a modified mRNA, or a cell or a pharmaceutical composition of the present invention, for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM- CSF deficiency in a subject or patient, wherein the nucleic acid is a low immunogenic nucleic acid, and wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. A further aspect of the invention relates to a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the modified nucleic acid is a polynucleotide comprises one or more of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or a functional fragment thereof; wherein the nucleic acid comprises one or more sequences encoding GM-CSF or a functional fragment thereof being delivered to and expressed in a target cell comprising a GM-CSF receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling). The invention also provides a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid or a cell or a pharmaceutical composition of the present invention. In general, all the features disclosed herein in the context of the nucleic acids and nucleic acids for use in a treatment apply mutatis mutandis to methods of treatment. In preferred embodiments, the GM-CSF deficiency or GM-CSF related disease is pulmonary alveolar proteinosis (PAP), more preferably, the GM-CSF deficiency is autoimmune PAP. In some embodiments, the PAP or autoimmune PAP may be caused or partially caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in the subject. In some embodiments, antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies may be present in a subject suffering from a GM-CSF deficiency such as PAP or autoimmune PAP. In some embodiments the invention relates to a method of treating (autoimmune) pulmonary alveolar proteinosis ((a)PAP) in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a nucleic acid, wherein the nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or a functional fragment thereof; wherein the nucleic acid comprising one or more sequences encoding GM-CSF or a functional fragment thereof is delivered to and expressed in a target cell (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling). In some embodiments, the nucleic acid comprises a sequence as shown in SEQ ID NO:1 or SEQ ID NO:45 or SEQ ID NO:8 or SEQ ID NO:75 or SEQ ID NO:28 or SEQ ID NO:64; or a sequence having 90% identity or greater, preferably 92% identity or greater, more preferably 95% identity or greater, more preferably 98% identity or greater; even more preferably 99% identity or greater. In some embodiments, the nucleic acid consists of a sequence as shown in SEQ ID NO:1 or SEQ ID NO:45 or SEQ ID NO:8 or SEQ ID NO:75 or SEQ ID NO:28 or SEQ ID NO:64. In some embodiments, the target cell is an immune cell or an airway epithelial cell or both. In preferred embodiments, the immune cell is selected from the list consisting of a macrophage, a goblet cell, a ciliate cell and/or combinations thereof. In some embodiments, the GM-CSF is expressed in the target cell for at least 6 hours, preferably for at least 12 hours; more preferably for at least 24 hours. A further aspect of the invention relates to a method for restoring the ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein, SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or an active fragment thereof to a target cell comprising said GM-CSF receptor or a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell and therefore allowing GM- CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. In some embodiments, said GM-CSF ligand protein once expressed is: a) transported to a cellular membrane and exposed to a GM-CSF receptor, preferably wherein said membrane is the cell membrane, or b) not transported to the cell membrane and bind the GM-CSF receptor in the intracellular environment. In preferred embodiments, the GM-CSF acts in an autocrine manner, and is optionally expressed in a granulocyte or a macrophage, preferably an alveolar macrophage. A further aspect of the invention relates to a nucleic acid according to the present invention encoding GM-CSF or a functional fragment thereof for use in a method for treatment or prevention of a disease caused by a GM-CSF deficiency. In preferred embodiments the disease caused by a GM-CSF deficiency is PAP. In more preferred embodiments, the PAP is aPAP. In an embodiment, the nucleic acids or vectors of the invention are used in a method of treatment of a GM-CSF related disease, preferably a disease caused by a lack of functional GM-CSF or preferably PAP and more preferably autoimmune PAP (aPAP). A further aspect of the invention relates to a nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), such as aPAP, interstitial lung disease such as idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. In certain embodiments, the aspergillosis is caused by Aspergillus fumigatus or/and Aspergillus flavus. Accordingly, the invention provides the nucleic acid as defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73 for use in the treatment of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), such as aPAP, interstitial lung disease such as idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. Preferably, the nucleic acid is a polyribonucleotide, preferably an mRNA. In an embodiment the mRNA sequence comprises a codon optimized GM-CSF sequence. In some embodiments, the nucleic acid is a nucleic acid of the invention. Preferably, the nucleic acid comprises a GM-CSF having an identity of 94% or more of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. More preferably, the nucleic acid is the nucleic acid of SEQ ID NO:1 or SEQ ID NO:45. In preferred embodiments, the nucleic acid is a polyribonucleotide, more preferably an mRNA, and most preferably a modified mRNA. In certain embodiments, said use is for the treatment of diseases caused by a deficient or defective production or absence of a functional GM-CSF. In certain embodiments said use is for the treatment of a disease caused by autoantibodies (aAbs) targeting GM-CSF, its receptor (also known as CD116 (Cluster of Differentiation 116), or both; In a more preferred embodiment, said disease is PAP; in a most preferred embodiment said use is in a method of treatment of autoimmune pulmonary alveolar proteinosis (aPAP). In certain embodiments, the nucleic acid, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or a fragment thereof for the use according to the invention is administered to a patient in need of treatment. In a preferred embodiment said patient in need of treatment is characterized by intraalveolar surfactant accumulation. In a preferred embodiment, said intraalveolar surfactant accumulation is determined by bronchoalveolar lavage fluid (BALF) turbidity. The skilled person possesses guidelines and standard method of obtaining and evaluating BALF, and its turbidity, usually obtained in 4-5 aliquots and knows that BALF turbidity correlates with age and disease severity. In some embodiments the treatment causes a significant reduction of BALF turbidity. In some embodiments, the patient has a GM-CSF deficiency. In certain embodiments, said a patient in need of treatment is characterized for being positive to the presence of autoantibodies directed to GM-CSF, more preferably, said patient have a positive serum GM-CSF level (>1.0 µg per milliliter) as described in Uchida, Kanji, et al. "Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis." Journal of immunological methods 402.1-2 (2014): 57-70, which is incorporated by reference herein. In some embodiments, the patient or subject in need of treatment is characterized for being positive to the presence of autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies. In some embodiments, the patient or subject in need of treatment suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies in the patient. In certain embodiments, the nucleic acid for use according to the invention is the nucleic acid as defined under “Nucleic acids” herein. Preferably said nucleic acid codes for a human GM-CSF. More preferably said human GM-CSF is a codon optimized GM-CSF. Most preferably said codon optimized GM-CSF is that of SEQ ID NO:1 or SEQ ID NO:45. In some embodiments, the disease to be treated is acute respiratory distress syndrome (ARDS), a severe inflammatory lung disease with high mortality. Unremitting lung inflammation predicts a poor prognosis for patients with ARDS, but pharmacotherapies designed to suppress inflammation have failed to improve outcomes. Although many cell types participate in tissue repair, macrophages have been shown to exhibit critical activity at all stages of repair and fibrosis due to their highly flexible programming. Thus, in some embodiments, the disease to be treated is ARDS. In certain embodiments, ARDS is treated by increasing the expression of GM-CSF, such as increasing mRNA expression. In preferred embodiments, increased mRNA GM-CSF expression occurs in alveolar macrophages. In some embodiments, the mRNA is an exogenous mRNA. Pulmonary idiopathic fibrosis (IPF), is a chronic lung disease characterized by the progressive development of fibrosis (scarring) in the lungs. This condition leads to the thickening and stiffening of lung tissue, making it difficult for the lungs to expand and perform their normal functions of exchanging oxygen and carbon dioxide. IPF is a form of interstitial lung disease, affecting the tissue and space around the alveoli in the lungs. The cause of IPF is not well understood. IPF typically affects older human adults and is a progressive disease. The disease can lead to decreased lung function, shortness of breath, coughing, and other respiratory symptoms, and can be life-threatening. There is currently no cure for IPF. Thus, in some embodiments, the disease to be treated is IPF. Depending on the local microenvironments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) phenotypes. In some embodiments, the disease is treated by polarizing the lung macrophages to M1 with the nucleic acid of the invention, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In some embodiments, the nucleic acid is a modified nucleic acid as defined herein. In some embodiments, together with a modified GM-CSF mRNA, a further modified mRNA expressing IFN-γ is administered to stimulate the generation of M1 macrophages and treat IPF. A further aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid encoding GM-CSF, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or a functional fragment thereof for use in a method for the treatment or prevention of a disease wherein the disease is selected from the list consisting of pulmonary alveolar proteinosis (PAP), acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, aspergillosis or fungal infections caused by Aspergillus sp., such fungal sinusitis, otomycosis, keratitis, and onychomycosis, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. In certain embodiments, the aspergillosis is caused by Aspergillus fumigatus or/and Aspergillus flavus. In preferred embodiments, the pharmaceutical composition is for use in the treatment of PAP. In a more preferred embodiment said PAP is autoimmune pulmonary alveolar proteinosis (aPAP). In certain embodiments, the nucleic acid of the invention molecule or the pharmaceutical composition for use according to the invention is administered topically or by injection, including intravenous injection. In certain embodiments the nucleic acid or the pharmaceutical composition for use according to the invention is administered by delivery into the respiratory system, preferably by inhalation. In certain embodiments said inhalation is inhalation of an aerosol comprising said nucleic acid or fragment thereof or said pharmaceutical composition. In some embodiments, the nucleic acid or the pharmaceutical composition is nebulized for administration. In some embodiments, a nucleic acid dose is about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day. Accordingly, in some embodiments, the patient or subject receives a nucleic acid dose of about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day, preferably via inhalation. In some embodiments, a nucleic acid dose comprised in a pharmaceutical composition is about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day. In certain embodiments, the nucleic acid, or the pharmaceutical composition for use according to the invention is delivered to a target cell, preferably said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is a granulocyte, a macrophage or both. In certain embodiments said GM-CSF is human GM-CSF. In certain embodiments the nucleic acid or the pharmaceutical composition for the use according to the invention is as defined above under “nucleic acids”. In certain embodiments, the nucleic acid, or the pharmaceutical composition for use according to the invention comprises an mRNA coding for GM-CSF is as shown in SEQ ID NO:1, SEQ ID NO:7, or SEQ ID NO:27. In certain embodiments, said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda, or alternatively In one aspect, the invention provides a nucleic acid defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73 for use in the treatment of PAP, autoimmune PAP, ARDS or IPF. In another aspect, the invention provides method of treatment comprising administering a nucleic acid defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73 to a subject, optionally wherein the subject is suffering from PAP, autoimmune PAP, ARDS or IPF. In another aspect, the invention provides a nucleic acid defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73 for use in the treatment of PAP or autoimmune PAP caused by or partially caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in the subject. In another aspect, the invention provides method of treatment comprising administering a nucleic acid defined in SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73 to a subject suffering from PAP or autoimmune PAP caused by or partially caused by the presence of antiGM-CSF autoantibodies or GM-CSF neutralizing antibodies in the subject. Any of the treatments disclosed herein can result in one or more of the following: (i) dose-dependent increases of GM-CSF level in bronchoalveolar lavage fluid (BALF) in the presence of a PAP phenotype, (ii) improvement of BALF-related endpoints, including reduced turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts, (iii) a shift in the phenotype of macrophages from large, lipid-filled macrophages towards regular-sized macrophages with limited lipid or no lipid content, (iv) activation of GM-CSF downstream genes, (v) efficient STAT5 activation/phosphorylation via autocrine stimulation, (vi) efficient STAT5 activation/phosphorylation in human THP-1 macrophages in comparison to recombinant hGM-CSF, e.g. in presence of hGM-CSF-neutralizing antibodies. In particular, the above stated treatment results can ameliorate symptoms or prevent pathogenesis of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM- CSF deficiency as disclosed herein. In another aspect, the invention provides a method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising, obtaining a cell from the subject and/or from a donor and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof, and administering the cell into a subject. For example, “obtaining a cell” can mean “obtaining migrating immune cell(s) from blood”, such as a migrating monocyte. “Contacting the with a modified nucleic acid” can mean “exposing the cell to GM-CSG ex vivo”. Thereby causing expansion. Further, the cells can be administered to the patient. Upon administration, the cell(s) can find their final tissue of destination. The subject and/or donor preferably is a human. In some embodiments, the cell is autologous to the subject, such as that the cell is administered to the same subject as it is obtained from. In some embodiments the cell is allogeneic to the subject, such as that the cell is administered to another subject as it is obtained from. In some embodiments the cell is GM-CSF deficient, e.g. does not produce a sufficient amount of GM-CSF when compared to a wild type cell. In some embodiments the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell. In some embodiments the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell. In some embodiments the cell is a cell selected from the list consisting of adventitial fibroblast, alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell, fibromyocyte, goblet cell, ionocyte, lipofibroblast, lymphatic cell, mesothelial cell, myofibroblast, mucous cell, neuroendocrine cell, pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. In some embodiments, the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte, and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof. In some embodiments the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte. In a preferred embodiment the cell is an alveolar macrophage. In some embodiments, the nucleic acid is a nucleic acid of the present invention, such as a modified nucleic acid or a modified RNA or modified mRNA. In some embodiments, the nucleic acid is any one of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In another aspect, the invention provides a chemically modified mRNA coding for GM-CSF for use in a method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein or an active fragment thereof into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell, and/or allowing GM-CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. In another aspect, the invention provides a chemically modified mRNA encoding one or more GM- CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency, optionally comprising restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be delivered into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said target cell and allowing the one or more GM-CSF ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more GM-CSF ligand protein and its GM- CSF receptor. A further aspect of the invention relates to a chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency, optionally comprising restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF ligand protein, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39, or an active fragment thereof is to be delivered into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said target cell and allowing the one or more GM-CSF ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more GM-CSF ligand protein and its GM- CSF receptor. In preferred embodiments, said GM-CSF ligand protein once expressed: a) binds to a GM-CSF receptor in the external cell membrane, or b) binds to a GM-CSF receptor already intracellularly, optionally in intracellular membrane. In certain embodiments, the GM-CSF ligand protein acts in an autocrine manner, and is optionally expressed in a granulocyte or a macrophage, preferably an alveolar macrophage. In certain embodiments, restoration the ligand-receptor interaction causes one or more of the effects selected from the list consisting of development and maintenance of pulmonary alveolar macrophages (AM), bone-marrow production and differentiation of cells of the myeloid lineage, recruitment and differentiation of monocyte-derived dendritic cells (DCs) (including production of IL-23 and T_H17 polarization of T cells, conventional DC maturation and antigen presentation (including CD103-expressing DCs in skin and small intestine, M1 macrophage polarization (including proinflammatory cytokine production, phagocytosis, antigen presentation), neutrophil priming and activation (including phagocytosis, oxidative burst and nitric oxide production), myeloid-cell vascular-wall adhesion, vessel-wall accumulation and tissue trafficking, tumor growth inhibition, lgM antibody production by immune response activator (IRA) B cells, and nociception via sensory neurons. In preferred embodiments, the restoration the ligand-receptor interaction causes M1 macrophage polarization and/or development and maintenance of pulmonary alveolar macrophages. In another aspect, the invention provides a chemically modified mRNA encoding one or more GM- CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency, the method comprising contacting a cell with the chemically modified mRNA or administering the chemically modified mRNA to a subject/patient. In some embodiments a subject/patient having a GM-CSF deficiency does not produce a sufficient amount of GM-CSF when compared to a healthy subject. In some embodiments the cells to be treated in a subject/patient are cells selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell. In some embodiments the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell. In some embodiments the cells to be treated in a subject/patient is a cell selected from the list consisting of adventitial fibroblast; alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell, fibromyocyte, goblet cell, ionocyte, lipofibroblast, lymphatic cell, mesothelial cell, myofibroblast, mucous cell, neuroendocrine cell, pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. In some embodiments, a cell to be treated in a subject/patient is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte; and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof. In some embodiments a cell to be treated in a subject/patient is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte. In a preferred embodiment a cell to be treated in a subject/patient is an alveolar macrophage. In some embodiments, the chemically modified mRNA encoding one or more of GM-CSF ligand protein is a modified mRNA of the present invention. In some embodiments, the chemically modified mRNA encoding one or more of GM-CSF ligand protein comprises any one of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38 or SEQ ID NO:39. In general, the chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency described herein can comprise any of the modified mRNAs provided herein. Accordingly, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency. Uses A further aspect of the invention relates to the use of the nucleic acid, the expression vector or pharmaceutical composition according to the present invention in a method of activation and/or expansion of a macrophage and/or a granulocyte. The use may be in vivo, ex vivo or in vitro. Accordingly, a further aspect of the invention relates to an in-vitro or ex-vivo use of the nucleic acid, the expression vector or pharmaceutical composition according to the present invention in a method of activation and/or expansion of a macrophage and/or a granulocyte. Any of the uses disclosed herein may be ex vivo or in vitro. The present invention shows that a functional GM- CSF is essential for downstream activation of GM-CSF targets, that are required for cell expansion. In certain embodiments, the macrophage and/or the granulocyte are isolated from a patient, contacted with the nucleic acid, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, according to the invention, expanded ex vivo or in vitro, and reintroduced to the patient in need thereof. Known methods for extraction or isolation, in-vitro expansion, and reintroduction into the patient are known for the skilled person, e.g. in the field of CAR-T cell technology. In some embodiment, the use does not comprise an isolation of a macrophage and/or the granulocyte from a patient. In some embodiments, the use does not comprise the reintroduction of the macrophage and/or the granulocyte into the patient. In some embodiments all steps of the use are performed in vitro or ex vivo. In general, the uses described herein can comprise any of the nucleic acids provided herein. Accordingly, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the nucleic acid when comprised in a use provided herein. Methods In one aspect, the invention provides a method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein or an active fragment thereof into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell and therefore allowing GM- CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. A further aspect of the invention relates to a method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein, such as SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73, or an active fragment thereof into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell and therefore allowing GM- CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. In some embodiments, the method can be in vivo. In some embodiments, the method can be in vitro or ex vivo. In preferred embodiments, said GM-CSF ligand protein once expressed: a) binds to a GM-CSF receptor in the external cell membrane, or b) binds to a GM-CSF receptor already intracellularly, optionally in intracellular membrane. In certain embodiments, the GM-CSF acts in an autocrine manner, and is optionally expressed in a granulocyte or a macrophage, preferably an alveolar macrophage. In certain embodiments, restoration the ligand-receptor interaction causes one or more of the effects selected from the list consisting of development and maintenance of pulmonary alveolar macrophages (AM), bone-marrow production and differentiation of cells of the myeloid lineage, recruitment and differentiation of monocyte-derived dendritic cells (DCs) (including production of IL-23 and T_H17 polarization of T cells, conventional DC maturation and antigen presentation (including CD103-expressing DCs in skin and small intestine, M1 macrophage polarization (including proinflammatory cytokine production, phagocytosis, antigen presentation), neutrophil priming and activation (including phagocytosis, oxidative burst and nitric oxide production), myeloid-cell vascular-wall adhesion, vessel-wall accumulation and tissue trafficking, tumor growth inhibition, lgM antibody production by immune response activator (IRA) B cells, and nociception via sensory neurons. In preferred embodiments, the restoration the ligand-receptor interaction causes M1 macrophage polarization and/or development and maintenance of pulmonary alveolar macrophages. In another aspect, the invention provides an ex vivo or in vitro method for expressing GM-CSF in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof. In some embodiments the cell is GM-CSF deficient, e.g. does not produce a sufficient amount of GM-CSF when compared to a wild type cell. In some embodiments the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell. In some embodiments the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell. In some embodiments the cell is a cell selected from the list consisting of adventitial fibroblast; alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell, fibromyocyte, goblet cell, ionocyte, lipofibroblast, lymphatic cell, mesothelial cell, myofibroblast, mucous cell, neuroendocrine cell, pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. In some embodiments, the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte; and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof. In some embodiments the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte. In a preferred embodiment the cell is an alveolar macrophage. In some embodiments, the nucleic acid is a nucleic acid of the present invention, such as a modified nucleic acid or a modified RNA or modified mRNA. In some embodiments, the nucleic acid is any one of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. In general, the methods described herein can comprise any of the nucleic acids provided herein. Accordingly, the features described in context of the nucleic acids provided herein apply mutatis mutandis to the nucleic acid when comprised in a method provided herein. Any of the methods provided herein can be in vitro or ex vivo. Routes of administration According to the invention, the nucleic acid, the vector, or the pharmaceutical composition thereof may be administered via one or more of the following routes of administration: intravenous, intraocular, intravitreal, intramuscular, subcutaneous, topical, oral, transdermal, intraperitoneal, intraorbital, by implantation, by inhalation, intrathecal, intraventricular, via the ear, or intranasal. Preferably the administration is topical, intranasal and/or by inhalation. Most preferably the administration is by inhalation. In a preferred embodiment, the nucleic acid or pharmaceutical composition of the present invention is nebulized and (to be) administered by inhalation. The nucleic acid or pharmaceutical composition of the present invention is preferably administered by delivery into the respiratory system. The delivery to the respiratory system is preferably by inhalation. The nucleic acid or pharmaceutical composition of the present invention is preferably nebulized for delivery/administration. When delivered to the respiratory system, the nucleic acid or pharmaceutical composition of the present invention can be nebulized. The nucleic acid or pharmaceutical composition of the present invention can be delivered to a target cell or a tissue comprising said target cell, preferably wherein said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is an alveolar epithelial cell, a granulocyte, or an alveolar macrophage. The nucleic acid or pharmaceutical composition of the present invention may also be delivered (and expressed) to a target cell comprising a GM-CSF receptor (autocrine signaling) and/or may be delivered (and expressed) to a neighbor cell to said target cell (paracrine signaling). The disclosure also encompasses embodiments where an additional therapeutic agent may be administered together with the nucleic acid, the vector, or the composition of the invention. The additional therapeutic agent may be formulated in the same pharmaceutical composition as the nucleic acid, or the vector of the invention. The additional therapeutic agent may be administered concurrently, but in a separate formulation or sequentially with the nucleic acid, or the vector of the invention. In other embodiments, the additional therapeutic agent may be administered at different times prior to or after administration of the nucleic acid, or the vector of the invention. Kits and articles of manufacture In a further aspect the present disclosure provides kits comprising any one or more of the nucleic acids, the vector, the cell, and/or the pharmaceutical composition described herein. The kit may comprise as a first component a nucleic acid of the present invention, a cell of the present invention or a pharmaceutical composition of the present invention and as a second component a delivery device, preferably wherein the delivery device is a nebulizer. The kit may further comprise an instruction leaflet, product insert, or information and directions for use in accordance with the technical teachings herein. In general, the kits provided herein can comprise any of the nucleic acids, cells or pharmaceutical compositions provided herein. Accordingly, the features described in context of the nucleic acids, cells or pharmaceutical compositions provided herein apply mutatis mutandis to the nucleic acids, cells or pharmaceutical compositions when comprised in a kit. The present invention refers to the following nucleotide and amino acid sequences: hGM-CSF ORF (DNA (SEQ ID NO:45) + RNA (SEQ ID NO:1) Sequence) ATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCCCGCCAGAAGCCCCA GCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTGCTGAACCTGAGCAG AGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACCTGCAAGAGCCCACC TGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAGCTGAAGGGCCCCC TGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGCTGTGCCACCCAGAT CATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTTTTGACTGCTGGGAA CCTGTGCAGGAGTGA Amino Acid Sequence hGM-CSF (SEQ ID NO:2) MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPT CLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWE PVQE 5’ UTR (part of initiation domain of T7 promotor + MinUTR-C + Kozak (DNA (SEQ ID NO:46) + RNA (SEQ ID NO: 3) Sequence) GGGAGACGCCACC DNA Sequence of T7 Promoter (without part of initiation domain of T7 promotor) (SEQ ID NO:4) TAATACGACTCACTATA Sequence upstream of start codon (minUTR-C)(DNA Sequence)(SEQ ID NO:5) TAATACGACTCACTATAGGGAGACGCCACC DNA Sequence of cloned hGM-CSF unit in transcription vector (SEQ ID NO:6) AAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTCACTATAGGGAGACGCCA CCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCCCGCCAGAAGCCC CAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTGCTGAACCTGAGC AGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACCTGCAAGAGCCCA CCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAGCTGAAGGGCCC CCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGCTGTGCCACCCAG ATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTTTTGACTGCTGGG AACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCTTCGAAGTGACTATCGG ATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTT hGM-CSF mRNA after IVT (RNA Sequence) (SEQ ID NO:7) GGGAGACGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCCC GCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTGC TGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACCT GCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAG CTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGCT GTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTTT TGACTGCTGGGAACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA Underlined = restriction sites (AAGCTT = HindIII, GAATTC = EcoRI, TTCGAA = BstBI) Bold = Start / Stop codon Cursive TAATACGACTCACTATAGGGAGA = T7 Promoter Underlined: GCCACC = Kozak Sequence Underlined and cursive = Primer binding Transcription vector of codon optimized hGM-CSF (p388) DNA (SEQ ID No: 8) + RNA (SEQ ID NO:75) TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCT GTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGG CTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGAT GCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATC GGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTA ACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCGAGCTCGGTACCTCGCGAA TGCATCTAGATGTGACTAAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTC ACTATAGGGAGACGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGC GCCCCCGCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGC GGCTGCTGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTT CGACCTGCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTC ACCAAGCTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGA CCAGCTGTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGAT TCCTTTTGACTGCTGGGAACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTC TTCGAAGTGACTATCGGATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTTGGCGTAATCATGG TCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAA AGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTT CCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGT ATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTAT CAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGC AAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCC CCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACC AGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTC CGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAG GTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTA ACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGAT TAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGA AGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGAT CCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAA AGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAA GGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTA AATCAAGCCCAATCTGAATAATGTTACAACCAATTAACCAATTCTGATTAGAAAAACTCATCGAGCATCA AATGAAACTGCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATGA AGGAGAAAACTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTCGT CCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGAG TGACGACTGAATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCC ATTACGCTCGTCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGCGAGA CGAAATACGCGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAATGCAACCGGCGCAGGAACACTG CCAGCGCATCAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACCTGGAATGCTGTTTTTCCGGG GATCGCAGTGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGAGGCATA AATTCCGTCAGCCAGTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGTT TCAGAAACAACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCGCACCTGATTGCCCGACATT ATCGCGAGCCCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTCC CGTTGAATATGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGATG ATATATTTTTATCTTGTGCAATGTAACATCAGAGATTTTGAGACACGGGCCAGAGCTGCA DNA (SEQ ID No: 47) + RNA (SEQ ID NO:9) Sequence of mGMCSF-opt7 Sequence ATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCCCTACCCGCAGCCCCA TCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCTGCTGGACGACATGCC CGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAAGCTGACCTGCGTGCAG ACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAAGGGCGCCCTGAACATGA CCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAGACCCAGGTGACCACCTA CGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAGTGCAAGAAGCCCGGCCAG AAGTGAGGATCC Amino acid sequence of murine GM-CSF (SEQ ID No: 10) MWLQNLLFLGIVVYSLSAPTRSPITVTRPWKHVEAIKEALNLLDDMPVTLNEEVEVVSNEFSFKKLTCVQ TRLKIFEQGLRGNFTKLKGALNMTASYYQTYCPPTPETDCETQVTTYADFIDSLKTFLTDIPFECKKPGQ K DNA (SEQ ID No: 48) + RNA (SEQ ID NO:11) Sequence of mGM-CSF GGGAGACGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCCCT ACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCTGC TGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAAGCT GACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAAGGGC GCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAGACCC AGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAGTGCAA GAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTC DNA (SEQ ID No: 49) / RNA (SEQ ID NO: 12) Sequence mGMCSF-opt2 mRNA Sequence after IVT from plasmid including Poly(A)tail - 599 nt GGGAGACGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCCCT ACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCTGC TGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAAGCT GACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAAGGGC GCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAGACCC AGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAGTGCAA GAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCTTCGAAAAAAAAAAA

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA sequence of Transcription vector for codon optimized mGM-CSF P398 (SEQ ID No: 13) TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCT GTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGG CTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGAT GCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATC GGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTA ACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCGAGCTCGGTACCTCGCGAA TGCATCTAGATGTGACTAAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTC ACTATAGGGAGACGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGC GCCCCTACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGA ACCTGCTGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAA GAAGCTGACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTG AAGGGCGCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCG AGACCCAGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGA GTGCAAGAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCTTCGAAGTG ACTATCGGATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTTGGCGTAATCATGGTCATAGCTG TTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAG CCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGG AAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGC TCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACT CAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCA GCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAG CATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTC CCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCT CCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGC TCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTC TTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGC GAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTA TTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAAC AAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCA AGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTG GTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAAGCC CAATCTGAATAATGTTACAACCAATTAACCAATTCTGATTAGAAAAACTCATCGAGCATCAAATGAAACT GCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATGAAGGAGAAAA CTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTCGTCCAACATCA ATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGAGTGACGACTG AATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCCATTACGCTC GTCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGCGAGACGAAATACG CGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAATGCAACCGGCGCAGGAACACTGCCAGCGCAT CAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACCTGGAATGCTGTTTTTCCGGGGATCGCAGT GGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGAGGCATAAATTCCGTC AGCCAGTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGTTTCAGAAACA ACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCGCACCTGATTGCCCGACATTATCGCGAGC CCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTCCCGTTGAATA TGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGATGATATATTTT TATCTTGTGCAATGTAACATCAGAGATTTTGAGACACGGGCCAGAGCTGCA DNA (SEQ ID NO: 50) / RNA (SEQ ID NO: 14) Sequence of 3’ UTR 30 nt CACCGGGCAATACGAGCTCAAGCCAGTCTC DNA (SEQ ID NO: 51) / RNA (SEQ ID NO: 15) Sequence of 5´CYBA UTR 37 nt CCGCGCCTAGCAGTGTCCCAGCCGGGTTCGTGTCGCC DNA (SEQ ID NO: 52) / RNA (SEQ ID NO: 16) Sequence of 3´CYBA UTR CCTCGCCCCGGACCTGCCCTCCCGCCAGGTGCACCCACCTGCAATAAATGCAGCGAAGCCGGG DNA (SEQ ID NO: 53) / RNA (SEQ ID NO: 17) Sequence of 5’ UTR (T7 promoter Initiation domain + Min UTR-C + TISU) + Start codon – 13 nt GGGAGACGCCAAGATG DNA (SEQ ID NO: 54) / RNA (SEQ ID NO: 18) Sequence of Human alpha globin 5´UTR – 31 nt CTCTTCTGGTCCCCACAGACTCAGAGAGAAC DNA (SEQ ID NO: 55) / RNA (SEQ ID NO: 19) sequence of 5´UTR 138 nt CCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCT CCGCGGCCGGGAACGGTGCATTGGAACGCGGATTCCCCGTGCCAAGAGTGACTCACCGTCCTTGACACG DNA (SEQ ID NO: 56) / RNA (SEQ ID NO: 20) Sequence of 3´UTR – 86 nt CCCCTCCCCAGTGCCTCTCCTGGCCCTGGAAGTTGCCACTCCAGTGCCCACCAGCCTTGTCCTAATAAA ATTAAGTTGCATCTTCG DNA (SEQ ID NO: 57) / RNA (SEQ ID NO: 21) Sequence of Min UTR-C + 5´SP30 Spacer CATTGAAATTTATCTCTTGTGTTGTGGTCGC DNA (SEQ ID NO: 58) / RNA (SEQ ID NO: 22) Sequence of 5´ UTR – 35 nt TAAGAGAGAAAAGAAGAGTAAGAAGAAATATAAGA DNA (SEQ ID NO:59) / RNA (SEQ ID NO:23) Sequence upstream of start codon – CT TAATACGACTCACTATA GGGAGA CT GCCACC DNA (SEQ ID NO: 60) / RNA (SEQ ID NO: 24) Sequence of 5´SP30 Spacer + MinUTR- CT - 32 nt CTATTGAAATTTATCTCTTGTGTTGTGGTCGC DNA (SEQ ID NO: 61) / RNA (SEQ ID NO: 25) Sequence of 5’ UTR (T7 promoter Initiation domain +MinUTR-CT +5´TISU GGGAGACTGCCAAG DNA (SEQ ID NO:62) / RNA (SEQ ID NO:26) Sequence of cloned unit in transcription vector + CT - 601 nt AAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTCACTATAGGGAGACTGCC ACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCCCGCCAGAAGCC CCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTGCTGAACCTGAG CAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACCTGCAAGAGCCC ACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAGCTGAAGGGCC CCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGCTGTGCCACCCA GATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTTTTGACTGCTGG GAACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCTTCGAAGTGACTATCG GATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTT DNA (SEQ ID NO:63) / RNA (SEQ ID NO:27) Sequence of hGM-CSF mRNA after IVT - CT GGGAGACTGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCC CGCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTG CTGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACC TGCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAA GCTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGC TGTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTT

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA (SEQ ID No: 28) / RNA (SEQ ID No: 64) Sequence of Transcription vector for codon optimized hGM-CSF -CT TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCT GTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGG CTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGAT GCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATC GGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTA ACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCGAGCTCGGTACCTCGCGAA TGCATCTAGATGTGACTAAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTC ACTATAGGGAGACTGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAG CGCCCCCGCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGG CGGCTGCTGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGT TCGACCTGCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCT CACCAAGCTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAG ACCAGCTGTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGA TTCCTTTTGACTGCTGGGAACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCT CTTCGAAGTGACTATCGGATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTTGGCGTAATCATG GTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATA AAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTT TCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCG TATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTA TCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAG CAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCC CCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATAC CAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGT CCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTA GGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGT AACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGA TTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAG AAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGA TCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAA AAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTA AGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTT AAATCAAGCCCAATCTGAATAATGTTACAACCAATTAACCAATTCTGATTAGAAAAACTCATCGAGCATC AAATGAAACTGCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATG AAGGAGAAAACTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTCG TCCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGA GTGACGACTGAATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGC CATTACGCTCGTCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGCGAG ACGAAATACGCGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAATGCAACCGGCGCAGGAACACT GCCAGCGCATCAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACCTGGAATGCTGTTTTTCCGG GGATCGCAGTGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGAGGCAT AAATTCCGTCAGCCAGTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGT TTCAGAAACAACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCGCACCTGATTGCCCGACAT TATCGCGAGCCCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTC CCGTTGAATATGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGAT GATATATTTTTATCTTGTGCAATGTAACATCAGAGATTTTGAGACACGGGCCAGAGCTGCA DNA (SEQ ID No: 65) / RNA (SEQ ID No: 29) Sequence of mRNA Sequence mGM-CSF -CT- 476 nt GGGAGACTGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCCC TACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCTG CTGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAAGC TGACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAAGGG CGCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAGACC CAGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAGTGCA AGAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTC DNA (SEQ ID No: 66) / RNA (SEQ ID No: 30) Sequence of mGMCSF-opt7 mRNA Sequence after IVT including Poly(A)tail -CT 596 nt GGGAGACTGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCC CTACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCT GCTGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAA GCTGACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAA GGGCGCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAG ACCCAGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAG TGCAAGAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCAAAAAAAAAA

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA Sequence of Expression vector for codon optimized mGM-CSF P398 -CT- (SEQ ID No: 31) TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCCCGGAGACGGTCACAGCTTGTCT GTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGG CTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGAT GCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATC GGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTA ACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTCGAGCTCGGTACCTCGCGAA TGCATCTAGATGTGACTAAGCTTTAGCCGGCGTGGAAGGTAACAGCACCGCTGGAATTCTAATACGACTC ACTATAGGGAGACTGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAG CGCCCCTACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTG AACCTGCTGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCA AGAAGCTGACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCT GAAGGGCGCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGC GAGACCCAGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCG AGTGCAAGAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCTTCGAAGT GACTATCGGATCCCGGGCCCGTCGACTGCAGAGGCCTGCATGCAAGCTTGGCGTAATCATGGTCATAGCT GTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAA GCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGG GAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCG CTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCAC TCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCC AGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGA GCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTT CCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTC TCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCG CTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGT CTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAG CGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGT ATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAA CAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTC AAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTT GGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAAGC CCAATCTGAATAATGTTACAACCAATTAACCAATTCTGATTAGAAAAACTCATCGAGCATCAAATGAAAC TGCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATGAAGGAGAAA ACTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTCGTCCAACATC AATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGAGTGACGACT GAATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCCATTACGCT CGTCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGCGAGACGAAATAC GCGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAATGCAACCGGCGCAGGAACACTGCCAGCGCA TCAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACCTGGAATGCTGTTTTTCCGGGGATCGCAG TGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGAGGCATAAATTCCGT CAGCCAGTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGTTTCAGAAAC AACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCGCACCTGATTGCCCGACATTATCGCGAG CCCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTCCCGTTGAAT ATGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTATTGTTCATGATGATATATTT TTATCTTGTGCAATGTAACATCAGAGATTTTGAGACACGGGCCAGAGCTGCA DNA (SEQ ID No: 67) / RNA (SEQ ID No: 32) Sequence of EGFP-HA-STOP GGGAGACTCTTCTGGTCCCCACAGACTCAGAGAGAACCGCCACTAGGTTTCCAAGGGCGAAGAA CTGTTCACCGGCGTGGTGCCCATTCTGGTGGAACTGGATGGGGATGTGAACGGCCACAAGTTCA GCGTCAGCGGAGAAGGCGAAGGCGACGCCACATACGGAAAGCTGACCCTGAAGTTCATCTGCAC CACCGGCAAGCTGCCTGTGCCTTGGCCTACACTGGTCACCACACTGACATACGGCGTGCAGTGC TTCAGCAGATACCCCGACCATATGAAGCAGCACGACTTCTTCAAGAGCGCCATGCCTGAGGGCT ACGTGCAAGAGAGAACCATCTTCTTTAAGGACGACGGCAACTACAAGACCAGGGCCGAAGTGAA GTTCGAGGGCGACACCCTGGTCAACAGAATCGAGCTGAAGGGCATCGACTTCAAAGAGGACGGC AACATCCTGGGCCACAAGCTCGAGTACAACTACAACAGCCACAACGTGTACATCATGGCCGACA AGCAGAAAAACGGCATCAAAGTGAACTTCAAGATCCGGCACAACATCGAGGACGGCTCTGTGCA GCTGGCCGATCACTACCAGCAGAACACACCTATCGGCGACGGACCTGTGCTGCTGCCTGATAAC CACTACCTGAGCACACAGAGCGCCCTGAGCAAGGACCCTAACGAGAAGAGGGACCACATGGTGC TGCTGGAATTCGTGACAGCCGCTGGCATCACACTCGGCATGGACGAGCTTTACAAAGGCGGCGG AGGCAGCTACCCTTACGACGTGCCAGATTACGCCTGATTCG DNA (SEQ ID No: 68) / RNA (SEQ ID No: 33) Sequence of mGMCSF-opt2 mRNA Sequence after IVT from PCR including Poly(A)tail - 595 nt GGGAGACGCCACCATGTGGCTGCAGAACCTGCTGTTCCTGGGCATCGTGGTGTACAGCCTGAGCGCCCCT ACCCGCAGCCCCATCACCGTGACCCGCCCCTGGAAGCACGTGGAGGCCATCAAGGAGGCCCTGAACCTGC TGGACGACATGCCCGTGACCCTGAACGAGGAGGTGGAGGTGGTGTCCAACGAGTTCAGCTTCAAGAAGCT GACCTGCGTGCAGACCCGGCTGAAGATCTTCGAGCAGGGCCTGCGGGGCAACTTCACCAAGCTGAAGGGC GCCCTGAACATGACCGCCAGCTACTACCAGACCTACTGCCCCCCCACCCCCGAGACCGACTGCGAGACCC AGGTGACCACCTACGCCGACTTCATCGACAGCCTGAAGACCTTCCTGACCGACATCCCCTTCGAGTGCAA GAAGCCCGGCCAGAAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCAAAAAAAAAAAAAAA

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA (SEQ ID NO:69) / RNA (SEQ ID NO:34) Sequence of 5’ UTR (part of initiation domain from T7 promotor + MinUTR-CT + Kozak GGGAGACTGCCACC DNA (SEQ ID NO:70) / RNA (SEQ ID NO:35) Sequence of 5’ UTR (T7 promoter Initiation domain + Min UTR-CT + 5´TISU) – 16 nt GGGAGACTGCCAAG DNA Sequence of 5’ Sequence upstream of start codon (T7 minUTR-CT + Kozak) (SEQ ID NO:36)

TAATACGACTCACTATAGGGAGACTGCCACC DNA (SEQ ID NO:71) / RNA (SEQ ID NO:37) Sequence of 5’ UTR (T7 promoter Initiation domain + Min UTR-C + 5´TISU) – 16 nt GGGAGACGCCAAG DNA (SEQ ID NO:72) / RNA (SEQ ID NO:38) Sequence of minUTR-C + Kozak +hGM- CSF mRNA after IVT with Segemented poly(A) GGGAGACGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCCC GCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTGC TGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACCT GCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAAG CTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGCT GTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTTT TGACTGCTGGGAACCTGTGCAGGAGTGAGGATCCCACCGGGCAATACGAGCTCAAGCCAGTCTCAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA (SEQ ID NO:73) / RNA (SEQ ID NO:39) Sequence of minUTR-CT + Kozak + hGM- CSF mRNA after IVT with Segmented poly(A) GGGAGACTGCCACCATGTGGCTGCAGAGCCTTCTGCTCCTGGGCACCGTGGCCTGCAGCATCAGCGCCCC CGCCAGAAGCCCCAGCCCTAGCACACAGCCCTGGGAGCACGTGAATGCCATCCAGGAAGCCAGGCGGCTG CTGAACCTGAGCAGAGACACAGCAGCTGAAATGAATGAAACTGTGGAGGTGATCAGTGAGATGTTCGACC TGCAAGAGCCCACCTGCCTCCAGACCAGACTGGAGCTGTACAAGCAGGGCCTGCGGGGCAGCCTCACCAA GCTGAAGGGCCCCCTGACCATGATGGCCAGCCACTACAAACAGCACTGCCCCCCCACACCTGAGACCAGC TGTGCCACCCAGATCATCACCTTTGAGAGCTTCAAGGAGAACTTGAAGGACTTCCTGCTGGTGATTCCTT

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DNA sequence upstream of T7 promoter (SEQ ID NO:40) TAATACGACTCACTATAGGGAGA DNA sequence upstream of T3 promoter (SEQ ID NO:41) AATTAACCCTCACTAAAGGGAGA DNA sequence upstream of start codon SP6 (SEQ ID NO:42) ATTTAGGTGACACTATAGAAG C DNA sequence upstream of start codon – K11 (SEQ ID NO:43) AATTAGGGCACACTATAGGGA DNA (SEQ ID NO:74)/ RNA (SEQ ID NO:44) sequence of Kozak consensus sequence (gcc)gccRccATGG The sequences provided herein above can comprise RNA and also the corresponding DNA equivalents, i.e. while SEQ ID NOs 1-44 relate to RNA sequences, it is apparent for the skilled person that the respective equivalent DNA sequence is identical to the RNA sequence (e.g. contains the same sequence information in relation to the encoded protein/amino acid sequence). The skilled person is aware that in an RNA uracil is present instead of thymine. For clarification, SEQ ID NOs 1-44 specifically refer to RNA and SEQ ID NOs: 45-74 additionally define the respective molecules provided herein above as DNA in the electronic ST.26 sequence listing. The invention provides the following items: 1. A nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably wherein the nucleic acid molecule comprises any of the following: (a1) a coding region, including a start codon at its 5’ end, coding for a codon optimized GM-CSF polypeptide having at least 94% identity to SEQ ID NO:1 or 45; and (a2) optionally a 5’ UTR upstream of said coding sequence, preferably wherein the 5’ UTR is a sequence selected from the list consisting of: the sequence GGGAGACGCCACC (SEQ ID NO:3 or 46), the sequence GGGAGACTGCCACC (SEQ ID NO:34 or 69), the sequence GGGAGACGCCAAG (SEQ ID NO:37 or 71), the sequence GGGAGACGCCAAG (SEQ ID NO:35 or 70), a CYBA 5´UTR (SEQ ID NO:15 or 51), 5´TISU UTR (GCCAAG), human alpha globin 5´UTR (SEQ ID NO:18 or 54), 5´UTR of SEQ ID NO:19 or 55, a SP30 Spacer 5´ UTR (SEQ ID NO:21 or 57) and/or the 5’ UTR of SEQ ID NO:22 or 58, and (a3) optionally when the nucleic acid is DNA, upstream of (a2) a promoter which is recognized by a DNA-dependent RNA polymerase, preferably a promoter with a sequence selected from TAATACGACTCACTATA (SEQ ID NO:4) which is recognized by a T7 DNA-dependent RNA polymerase, and (a4) optionally a 3’ UTR, preferably a 3’ UTR selected from 3’-UTR selected from the list consisting of: 3’UTR of the sequence 5’-TTCG-3’, the UTR sequence 5’- CACCGGGCAATACGAGCTCAAGCCAGTCTC (SEQ ID NO:14 or 50), CYBA 3´UTR (SEQ ID NO:16 or 52), and/or 3’ UTR of SEQ ID NO:20 or 56, and/or (a5) optionally a poly(A), preferably a segmented poly(A), preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. 2. The nucleic acid molecule according to item 1, wherein the nucleic acid molecule is selected from a polynucleotide DNA molecule or a polynucleotide RNA, preferably wherein said polynucleotide RNA is an mRNA. The nucleic acid according to anyone of items 1 or 2, wherein the nucleic acid is a modified nucleic acid comprising a combination of unmodified nucleosides and chemically modified nucleosides. The nucleic acid according to item 3, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic. The nucleic acid according to item 3 or 4, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2- thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio- 1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy- pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo- citosine and combinations thereof. The nucleic acid according to item 1 to 5, wherein the nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine. The nucleic acid according to anyone of items 1 to 5, wherein the nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1- methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine. The nucleic acid according to item 1 to 5, wherein the nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5- Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5- Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5-Iodocytidine. The nucleic acid according to anyone of items 1 to 5, wherein the nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). The nucleic acid according to anyone of items 2 to 9, wherein the modified mRNA encoding a GM-CSF is codon optimized, preferably wherein the modified mRNA is codon optimized for expression of GM-CSF in a human. The nucleic acid according to any one of items of item 1 to 10, wherein the nucleic acid is produced/transcribed using an in vitro system, such as in vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase. The nucleic acid according to any one of items 1 to 11, wherein the nucleic acid is comprised in a vector, preferably an expression vector, more preferably the vector of SEQ ID NO:8 or SEQ ID NO:75 or SEQ ID NO:28 or SEQ ID NO:64. A cell comprising a modified nucleic acid encoding a GM-CSF protein or a functional fragment thereof, preferably a nucleic acid according to items 1 to 12. The cell according to item 13, wherein the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell. The cell according to item 14, wherein the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell. The cell according to anyone of items 13 to 15, wherein the cell is a cell selected from the list consisting of adventitial fibroblast; alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell; fibromyocyte, goblet cell; ionocyte; lipofibroblast, lymphatic cell, mesothelial cell; myofibroblast; mucous cell, neuroendocrine cell; pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. The cell according to anyone of items 13 to 16, wherein the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte; and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof. The cell according to anyone of items 13 to 17, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte. The cell according to item 18 wherein the cell is an alveolar macrophage. A pharmaceutical composition comprising the nucleic acid of any one of items 1-12. The pharmaceutical composition according to item 20, wherein the nucleic acid is in the form of a lipid nanoparticle (LNP) or a lipidoid nanoparticle (LiNP) formulation. The pharmaceutical composition according to any one of item 20 or 21, wherein the composition comprises a lipidoid nanoparticle formulation comprising: a) a nucleic acid coding for GM-CSF b) a cationic lipidoid of formula (b-V), and

c) one or more helper lipid(s), optionally selected from: c1) DPPC, and/or c2) cholesterol, and/or c3) PEG-lipid DMG-PEG2000, and optionally d) a triblock copolymer, preferably, components b) and c1-c3) are present, more preferably they are at the molar ratios of about (4-10):(4-7):(3-6):(0.3-3), preferably about (6-9):(4-7):(3-6):(0.3-3), more preferably about 8:(4-7):(3-6):(0.3-3), even more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively. The pharmaceutical composition according to any one of items 20 to 22, wherein: a) said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma and/or b) wherein the pharmaceutical composition or polyribonucleotide is administered once to three times a week, preferably three times a week, for at least 1 week, preferably for at least 2 weeks, more preferably for at least 3 weeks and even more preferably for at least 4 weeks, and/or c) wherein the pharmaceutical composition when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of about 200 µg to about 15 mg, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day. The nucleic acid according to any one of items 1 to 12, or the cell according to any of items 13 to 19, or the pharmaceutical composition of any one of items 20 to 23 for use as a medicament. A modified nucleic acid encoding GM-CSF or a functional fragment thereof or the pharmaceutical composition of any one of items 20 to 23 or the cell of any one of items 13 to 19 for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM- CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient. The modified nucleic acid or the pharmaceutical composition or the cell for use according to item 25, wherein the modified nucleic acid molecule is a polyribonucleotide, preferably an mRNA. The modified nucleic acid or the pharmaceutical composition or the cell for use according to item 25 or 26, wherein the modified nucleic acid is a low-immunogenic nucleic acid. The modified nucleic acid or the pharmaceutical composition or the cell for use according to item 27, wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 28, wherein the nucleic acid comprises a chemically modified nucleoside selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 28, wherein the nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5- methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 28, wherein the nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1- methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 28, wherein the nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5-Iodocytidine. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of items 26 to 32, wherein the modified mRNA is a codon optimized GM-CSF, preferably wherein the modified mRNA is codon optimized for expression of GM- CSF in a human. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 28, wherein the nucleic acid is as defined in any one of items 1 to 12. The nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 34, wherein the GM-CSF deficiency, the GM-CSF related disease or the disease caused by a GM-CSF deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. The modified nucleic acid molecule or the pharmaceutical composition or the cell for the use according to item 35, wherein the disease is PAP, preferably aPAP. The nucleic acid molecule or the pharmaceutical composition or the cell for the use according to any one of items 25 to 36, wherein the disease to be treated is a PAP related to a defective or deficient GM-CSF production or a defective or deficient GM-CSF receptor function. The nucleic acid molecule or the pharmaceutical composition or the cell for use according to item 35, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis. The modified nucleic acid molecule or fragment thereof or the pharmaceutical composition or the cell for use according to anyone of items 25 to 38, wherein the nucleic acid is produced using an in-vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase. The nucleic acid molecule or the pharmaceutical composition or the cell for use of any one of items 25 to 39, wherein the nucleic acid molecule, or the cell, or the pharmaceutical composition is administered to the patient in need of treatment, preferably via inhalation. The nucleic acid molecule or the pharmaceutical composition or the cell for use according to any one of items 25 to 40, wherein the patient in need of treatment is characterized by intraalveolar surfactant accumulation. The nucleic acid molecule or the pharmaceutical composition or the cell for use according to item 41, wherein the intraalveolar surfactant accumulation is determined by bronchoalveolar lavage fluid turbidity. The nucleic acid or the pharmaceutical composition or the cell for use according to any one of items 40 to 42, wherein the patient in need of treatment is characterized for being positive to the presence of autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies, optionally wherein the patient suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM- CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies in the patient. The nucleic acid or the pharmaceutical composition or the cell for use according to any one of items 40 to 43, wherein the patient in need of treatment receives via inhalation a nucleic acid dose of about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day. A pharmaceutical composition comprising a modified nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. The pharmaceutical composition according to item 45, wherein the modified nucleic acid molecule is selected from a polynucleotide DNA molecule or a polynucleotide RNA molecule, preferably wherein said polynucleotide RNA molecule is an mRNA molecule. The pharmaceutical composition according to anyone of items 45 or 46, wherein the modified nucleic acid comprises a combination of unmodified nucleosides and chemically modified nucleosides. The pharmaceutical composition according to item 47, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic. The pharmaceutical composition according to item 47 or 48, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof. The pharmaceutical composition according to items 45 to 49, wherein the modified nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine. The pharmaceutical composition according to items 45 to 49, wherein the modified nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1-methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine. The pharmaceutical composition according to items 45 to 49, wherein the modified nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5- Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5- Iodocytidine. The pharmaceutical composition according to items 45 to 49, wherein the modified nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). The pharmaceutical composition according to items 45 to 53, wherein the modified nucleic acid comprises a nucleic acid sequence, preferably a nucleic acid sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. The pharmaceutical composition for use according to anyone of items 45 to 54, wherein: a) the PAP is autoimmune pulmonary alveolar proteinosis (aPAP) and/or b) the viral infection is influenza, SARS, or Covid, and/or c) the pulmonary fibrosis is idiopathic pulmonary fibrosis The pharmaceutical composition for use according to anyone of items 45 to 55, wherein the composition comprises: a) a nucleic acid coding for GM-CSF, b) a cationic lipidoid, optionally a lipidoid of formula (b-V), and

c) one or more helper lipid(s), optionally selected from: c1) DPPC, and/or c2) cholesterol, and/or c3) PEG-lipid DMG-PEG2000, and optionally d) a triblock copolymer, optionally, when b), and c1)-c3) are present, they are at the molar ratios of about (4-10):(4- 7):(3-6):(0.3-3), preferably about (6-9):(4-7):(3-6):(0.3-3), more preferably about 8:(4-7):(3- 6):(0.3-3), more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively,, preferably, all b), c1)-c3) and d) compositions are present. The nucleic acid molecule for use according to any one of items 25 to 44, or the cell for use according to any one of items 25 to 44, or the pharmaceutical composition for use according to any one of items 25 to 56, wherein the nucleic acid or the pharmaceutical composition is to be administered by delivery into the respiratory system. The nucleic acid molecule for use according to any one of items 25 to 44 and 57, or the cell for use of any one of items 25 to 44 and 57, or the pharmaceutical composition for use of any one of items 25 to 57, wherein said delivery into the respiratory system is by inhalation. The nucleic acid molecule for use of item 58, or the cell for use of item 58, or the pharmaceutical composition for use of item 58, wherein said inhalation is inhalation of an aerosol comprising said nucleic acid or said pharmaceutical composition. The nucleic acid molecule for use of any one of items 25 to 44 and 57 to 59, or the cell for use according to any one of items 25 to 44 and 57 to 59, or the pharmaceutical composition for use according to any one of items 25 to 59, wherein said nucleic acid, or cell, or pharmaceutical composition is delivered to a target cell or a tissue comprising said target cell, preferably wherein said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is an alveolar epithelial cell, a granulocyte, or an alveolar macrophage. The pharmaceutical composition for the use according to any one of items 45 to 60, wherein said nucleic acid is as defined in any one of items 1 to 12. The pharmaceutical composition according to any one of items 20 to 23 or the pharmaceutical composition for use according to any one of items 25 to 61 wherein said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma. The nucleic acid molecule for use of any one of items 25 to 44 and 57 to 60, or the cell for use according to any one of items 25 to 44 and 57 to 60, or the pharmaceutical composition for use according to any one of items 25 to 62, wherein the treatment results in one or more of: (i) dose-dependent increases of GM-CSF level in bronchoalveolar lavage fluid (BALF) in the presence of a PAP phenotype, (ii) improvement of BALF-related endpoints, including reduced turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts, (iii) a shift in the phenotype of macrophages from large, lipid-filled macrophages towards regular-sized macrophages with limited lipid or no lipid content, (iv) activation of GM-CSF downstream genes, (v) efficient STAT5 activation/phosphorylation via autocrine stimulation, (vi) efficient STAT5 activation/phosphorylation in human THP-1 macrophages in comparison to recombinant hGM-CSF, e.g. in presence of hGM-CSF-neutralizing antibodies. Use of the nucleic acid, the expression vector or the pharmaceutical composition according to anyone of the preceding items in a method of activation and/or expansion of a macrophage, a monocyte and/or a granulocyte. The use according to item 64, wherein the macrophage, the monocyte and/or the granulocyte activation and/or expansion occurs in-vitro or ex-vivo. The use according to any one of items 64 or 65, wherein the macrophage is an alveolar macrophage and the monocyte is a migrating monocyte. A method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof; wherein the nucleic acid comprises one or more sequences encoding GM-CSF or a functional fragment thereof being delivered to and expressed in a target cell comprising a GM-CSF receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling). The method according to item 67, wherein the modified nucleic acid molecule is selected from a polynucleotide DNA molecule or a polynucleotide RNA molecule, preferably wherein said polynucleotide RNA molecule is an mRNA molecule. The method according to anyone of items 67 or 68, wherein the modified nucleic acid comprises a combination of unmodified nucleosides and chemically modified nucleosides. The method according to item 69, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic. The method according to item 70, wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid. The method according to anyone of items 69 to 71, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof. The method according to anyone of items 69 to 71, wherein the modified nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine. The method according to anyone of items 69 to 71, wherein the modified nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1-methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine. The method according to anyone of items 69 to 71, wherein the modified nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5- Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5- Iodocytidine. The method according to anyone of items 69 to 71, wherein the modified nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). The method according to anyone of items 67 to 76, wherein the modified nucleic acid comprises a nucleic acid sequence, preferably a nucleic acid sequence encoding a GM- CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. The method according to anyone of items 68 to 77, wherein the modified nucleic acid is an mRNA codon optimized for expression of GM-CSF, preferably wherein the modified mRNA is codon optimized for expression of GM-CSF in a human. The method according to anyone of items 67 to 78, wherein the nucleic acid is as defined in any one of items 1 to 12. The method according to anyone of items 67 to 79, wherein the GM-CSF deficiency, the GM-CSF related disease or the disease caused by a GM-CSF deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof. The method according to anyone of items 67 to 80, wherein the disease is PAP, preferably aPAP. The method according to anyone of items 67 to 81, wherein the disease to be treated is a PAP related to a defective or deficient GM-CSF production or a defective or deficient GM- CSF receptor function. The method according to item 80, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis. The method according to anyone of items 67 to 83, wherein the nucleic acid is produced using an in-vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase. The method according to anyone of items 67 to 84, wherein the nucleic acid is administered by delivery into the respiratory system. The method according to item 85, wherein the nucleic acid is administered to the subject via inhalation. The method according to item 86, wherein said inhalation is inhalation of an aerosol comprising said nucleic acid. The method according to anyone of items 67 to 87, wherein a nucleic acid dose of about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day is administered to the subject via inhalation. The method according to anyone of items 67 to 88, wherein the subject is characterized by intraalveolar surfactant accumulation. The method according to item 89, wherein the intraalveolar surfactant accumulation is determined by bronchoalveolar lavage fluid turbidity. The method according to anyone of items 67 to 90, wherein the subject is characterized for being positive to the presence of autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM-CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies, optionally wherein the patient suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM- CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies in the patient. The method according to anyone of items 67 to 91, wherein said nucleic acid, is delivered to a target cell or a tissue comprising said target cell, preferably wherein said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is an alveolar epithelial cell, a granulocyte, or an alveolar macrophage. The method according to anyone of items 67 to 92, wherein the target cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, a migrating monocyte; and/or b) an alveolar cell, preferably an alveolar epithelial cell, a goblet cell, a ciliate cell and/or combinations thereof. The method according to any one of items 67 to 93, wherein GM-CSF is expressed in the target cell for at least 6 hours, preferably for at least 12 hours; more preferably for at least 24 hours. The method according to any one of items 67 to 94, wherein the method further comprises administering an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma. The method according to any one of items 67 to 95, wherein the method results in one or more of: (i) dose-dependent increases of GM-CSF level in bronchoalveolar lavage fluid (BALF) in the presence of a PAP phenotype, (ii) improvement of BALF-related endpoints, including reduced turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts, (iii) a shift in the phenotype of macrophages from large, lipid-filled macrophages towards regular-sized macrophages with limited lipid or no lipid content, (iv) activation of GM-CSF downstream genes, (v) efficient STAT5 activation/phosphorylation via autocrine stimulation, (vi) efficient STAT5 activation/phosphorylation in human THP-1 macrophages in comparison to recombinant hGM-CSF, e.g. in presence of hGM-CSF-neutralizing antibodies. A method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein or an active fragment thereof into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell, and/or allowing GM-CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. The method of item 97, wherein said GM-CSF ligand protein once expressed: a) binds to a GM-CSF receptor in a external cell membrane, and/or b) binds to a GM-CSF receptor already intracellularly, optionally in a intracellular membrane. The method according to any one of items 97 or 98, wherein GM-CSF act in an autocrine manner, optionally act in an autocrine manner in a granulocyte or a macrophage, preferably an alveolar macrophage. The method of anyone of items 97 to 99, wherein the method occurs ex-vivo or in vitro. A kit comprising the nucleic acid of any one of item 1 to 12, or the cell of any one of items 13 to 19, or the pharmaceutical composition of any one of items 20 to 23, and a delivery device, preferably wherein the delivery device is a nebulizer. A method of treating a GM-CSF deficiency in a subject in need thereof, the method comprising, obtaining a cell from the subject and/or from a donor and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof, and administering the cell into a subject. The method according to item 102, wherein the cell is autologous to the subject, such as that the cell is administered to the same subject as it is obtained from. The method according to item 102, wherein the cell is allogeneic to the subject, such as that the cell is administered to another subject as it is obtained from. An ex vivo or in vitro method for expressing a GM-CSF in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF or a functional fragment thereof. The method according to item 105, wherein the cell is GM-CSF deficient, e.g. does not produce a sufficient amount of GM-CSF when compared to a wild type cell. The method according to any one of items 102-106, wherein the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell. The method according to item 107, wherein the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell. The method according to any one of items 102 to 108, wherein the cell is a cell selected from the list consisting of adventitial fibroblast, alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell; fibromyocyte, goblet cell, ionocyte, lipofibroblast, lymphatic cell, mesothelial cell, myofibroblast; mucous cell, neuroendocrine cell; pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell. The method according to any one of items 102 to 109, wherein the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte, and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof. 111. The method according to any one of items 102 to 110, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte. 112. The method according to item 111, wherein the cell is an alveolar macrophage. 113. The method according to anyone of items 102 to 112, wherein the nucleic acid is as defined in any one of items 1 to 12. Furthermore, the invention relates to the following items: 1. A nucleic acid comprising a sequence encoding a GM-CSF protein or a functional fragment thereof, wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. 2. The nucleic acid according to item 1, wherein the nucleic acid is selected from a polynucleotide DNA or a polynucleotide RNA, preferably wherein said polynucleotide RNA is an mRNA, preferably, wherein the nucleic acid is a modified nucleic acid comprising a combination of unmodified nucleosides and chemically modified nucleosides, preferably, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic, preferably, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5- methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2- thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio- pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1- methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5- methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof. 3. The nucleic acid according to item 2, wherein the nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine, or wherein the nucleic acid comprises the chemically modified nucleoside N1- methylpseudouridine, preferably at least 1% N1-methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine, or wherein the nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5- Iodouridine and 3% 5-Iodocytidine, or wherein the nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ). The nucleic acid according to any one of items 1 to 3, further comprising any of the following: (a1) a 5' UTR upstream of the GM-CSF coding sequence, preferably wherein the 5' UTR is a sequence selected from the list consisting of: the sequence GGGAGACGCCACC (SEQ ID NO:3 or 46), the sequence GGGAGACTGCCACC (SEQ ID NO:34 or 69), the sequence GGGAGACGCCAAG (SEQ ID NO:37 or 71), the sequence GGGAGACGCCAAG (SEQ ID NO:35 or 70), a CYBA 5´UTR (SEQ ID NO:15 or 51), 5´TISU UTR (GCCAAG), human alpha globin 5´UTR (SEQ ID NO:18 or 54), 5´UTR of SEQ ID NO:19 or 55, a SP30 Spacer 5´ UTR (SEQ ID NO:21 or 57) and/or the 5' UTR of SEQ ID NO:22 or 58, and (a2) when the nucleic acid is DNA, upstream of (a1) a promoter which is recognized by a DNA-dependent RNA polymerase, preferably a promoter with a sequence selected from TAATACGACTCACTATA (SEQ ID NO:4) which is recognized by a T7 DNA-dependent RNA polymerase, and (a3) a 3' UTR, preferably a 3' UTR selected from 3'-UTR selected from the list consisting of: 3'UTR of the sequence 5'-TTCG-3', the UTR sequence 5'- CACCGGGCAATACGAGCTCAAGCCAGTCTC (SEQ ID NO:14 or 50), CYBA 3´UTR (SEQ ID NO:16 or 52), and/or 3' UTR of SEQ ID NO:20 or 56, and/or (a4) a poly(A), preferably a segmented poly(A). The nucleic acid according to any one of items 1 to 4, wherein the nucleic acid is comprised in a vector, preferably an expression vector, more preferably the vector of SEQ ID NO:8 or SEQ ID NO:75 or SEQ ID NO:28 or SEQ ID NO:64. A cell comprising the nucleic acid according to items 1 to 5, preferably, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte, most preferably, wherein the cell is an alveolar macrophage. A pharmaceutical composition comprising the nucleic acid of any one of items 1-5. The pharmaceutical composition according to item 7, wherein the nucleic acid is in the form of a lipid nanoparticle (LNP) or a lipidoid nanoparticle (LiNP) formulation, preferably, wherein the composition comprises a lipidoid nanoparticle formulation comprising: a) a nucleic acid coding for GM-CSF b) a cationic lipidoid of formula (b-V), and

c) one or more helper lipid(s), optionally selected from: c1) DPPC, and/or c2) cholesterol, and/or c3) PEG-lipid DMG-PEG2000, and optionally d) a triblock copolymer, preferably, components b) and c1-c3) are present, more preferably they are at the molar ratios of about (4-10):(4-7):(3-6):(0.3-3), preferably about (6-9):(4-7):(3-6):(0.3-3), more preferably about 8:(4-7):(3-6):(0.3-3), even more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively, optionally, wherein: a) said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma and/or b) wherein the pharmaceutical composition or polyribonucleotide is administered once to three times a week, preferably three times a week, for at least 1 week, preferably for at least 2 weeks, more preferably for at least 3 weeks and even more preferably for at least 4 weeks, and/or c) wherein the pharmaceutical composition when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of about 200 µg to about 15 mg, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day. The nucleic acid according to any one of items 1 to 5, or the cell according to item 6, or the pharmaceutical composition according to item 7 or 8 for use as a medicament. The nucleic acid according to any one of items 1 to 5, or the cell according to item 6, or the pharmaceutical composition according to item 7 or 8 for use in a method for the treatment or prevention of a GM-CSF deficiency, a GM-CSF related disease or a disease caused by a GM-CSF deficiency in a subject or patient. The nucleic acid or the cell or the pharmaceutical composition for the use according to item 10, wherein the GM-CSF deficiency, the GM-CSF related disease or the disease caused by a GM-CSF deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof, preferably, wherein the disease is PAP, most preferably aPAP. The nucleic acid or the cell or the pharmaceutical composition for use according to item 10 or 11, wherein the nucleic acid, or the cell, or the pharmaceutical composition is administered to the patient in need of treatment via inhalation, preferably, wherein the patient in need of treatment is characterized by intraalveolar surfactant accumulation, e.g. determined by bronchoalveolar lavage fluid turbidity, optionally, wherein the patient in need of treatment is characterized for being positive to the presence of autoantibodies directed to GM-CSF or to GM-CSF receptor, such as antiGM- CSF/antiGM-CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies, optionally wherein the patient suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM-CSF/antiGM- CSF receptor autoantibodies or GM-CSF/GM-CSF receptor neutralizing antibodies in the patient. A pharmaceutical composition comprising a modified nucleic acid encoding GM-CSF or a functional fragment thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp. An in-vitro or ex-vivo use of the nucleic acid, the expression vector or the pharmaceutical composition according to anyone of the preceding items in a method of activation and/or expansion of a macrophage, a monocyte and/or a granulocyte preferably, wherein the macrophage is an alveolar macrophage and the monocyte is a migrating monocyte. An ex-vivo or in vitro method for restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF ligand protein or an active fragment thereof into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF to act in an autocrine manner, or alternatively expressing GM-CSF in said neighboring cell, and/or allowing GM-CSF to act in a paracrine manner, and optionally c) allowing the GM-CSF to interact with its receptor and thereby restoring the interaction between the ligand GM-CSF and its receptor. A chemically modified mRNA encoding one or more GM-CSF ligand protein or an active fragment thereof for use in a method of treating a GM-CSF deficiency, optionally comprising restoring a ligand-receptor interaction between a GM-CSF ligand protein and a GM-CSF receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be delivered into a target cell comprising said GM-CSF receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said target cell and allowing the one or more GM-CSF ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF ligand protein or an active fragment thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF ligand protein is to be allowed to interact with its receptor and thereby restoring the interaction between the one or more GM-CSF ligand protein and its GM-CSF receptor. 17. An ex vivo or in vitro method for expressing a GM-CSF in a cell, the method comprising contacting a cell with the nucleic acid according to any one of items 1 to 5, preferably, wherein the cell is GM-CSF deficient, e.g. does not produce a sufficient amount of GM-CSF when compared to a wild type cell, preferably, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte, most preferably, wherein the cell is an alveolar macrophage. Furthermore, the invention relates to the following items: 1. A modified nucleic acid comprising the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C). 2. The nucleic acid according to item 1, wherein the nucleic acid is selected from a polynucleotide DNA or a polynucleotide RNA. 3. The nucleic acid according to item 1 or 2, wherein the nucleic acid is a RNA selected from the list of viral RNA, retroviral RNA, replicon RNA, small interfering RNA (siRNA), antisense RNA, CRISPR RNA e.g. gRNA or sgRNA, ribozymes, aptamers, riboswitches, immunostimulating RNA, transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), microRNA (miRNA), and/or Piwi-interacting RNA (piRNA), preferably wherein the RNA is a messenger RNA (mRNA). 4. The nucleic acid according to any one of items 1 to 3, wherein the nucleic acid comprises a combination of unmodified nucleosides and chemically modified nucleosides. 5. The nucleic acid according to any one of items 1 to 4, wherein the nucleic acid is low- immunogenic or non-immunogenic. 6. The nucleic acid according to any one of items 1 to 5, wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and between 1% and 50% 5-Iodocytidine. 7. The nucleic acid according to any one of items 1 to 6, wherein the nucleic acid comprises between 20%-40% 5-Iodouridine and 2%-5% 5-Iodocytidine. 8. The nucleic acid according to any one of items 1 to 7, wherein the nucleic acid comprises 30% 5-Iodouridine and 3% 5-Iodocytidine. 9. The nucleic acid according to any one of items 1 to 8, wherein the nucleic acid comprises a sequence encoding a GM-CSF, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated protein or any functional fragments thereof, preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73. 10. The nucleic acid according to any one of items 1 to 9, wherein the nucleic acid does not comprise chemically modified nucleosides other than 5-Iodouridine (I5U) and 5-Iodocytidine (I5C). The explanations and definitions provided herein for a chemically modified nucleic acid encoding GM-CSF, specifically a nucleic acid encoding GM-CSF comprising the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C) apply mutatis mutandis in this context. Other aspects and advantages of the invention will be described in the following examples, which are given for purposes of illustration and not by way of limitation. Each publication, patent, patent application or other document cited in this application is hereby incorporated by reference in its entirety.

EXAMPLES The following examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples. Rather, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that the skilled person can, using the preceding description, the following illustrative examples and the common general knowledge make use of the present invention. The following working examples point to some of the preferred embodiments of the present invention and are not to be construed as limiting in any way on the remainder of the disclosure. Example 1 Investigation of GM-CSF pathway activation The aim of the experiments described in this Example was to investigate activation of GM-CSF pathway in murine macrophage cell lines. Cell lines of interest were the murine macrophage cell line RAW 264.7 and the murine alveolar macrophages line AMJ2-C11. Cells were incubated with doses of 0.01-500 ng/mL recombinant murine GM-CSF (protein). Supernatant and cells were sampled after 0.5-24 h and analyzed using qPCR for investigation of target gene upregulation and GM-CSF ELISA for investigation of GM-CSF-uptake. Additionally, samples were collected for analysis using transcription factor PU.1 western blot and pSTAT5/STAT5- western blot. STAT5 is a downstream molecule of the GM-CSF receptor used to measure GM-CSF biological activity In RAW264.7 and AMJ2-C11 cells, GM-CSF pathway can be activated via recombinant GM-CSF or GM-CSF mRNA (murine GM-CSF, PCR-based IVT, 100% of N1-methyl-Pseudo-UTP). However, GM-CSF pathway activation can only be detected downstream, using western blot to show activation of STAT5 via phosphorylation upon treatment with GM-CSF. Evidence of pathway activation via upregulation of downstream targets cannot be detected using qPCR or western blot. Recombinant GM-CSF and GM-CSF mRNA are both able to overcome inhibition of STAT5 activation in presence of monoclonal GM-CSF neutralizing antibody at respective doses. Phosphorylated/activated STAT (pSTAT) was used in this experiment as a “proximal” marker for the pathway activation of downstream targets in vitro. Abbreviations & Definitions

. Materials and Methods .1 Materials i. Material for cell culture

ii. Material for ELISA

iii. Material for qPCR

iv. Material for western blot

v. Devices

1.2 Methods 1.2.1 Cultivation of RAW 264.7 The murine macrophage cell line RAW 264.7 was cultivated in DMEM (GlutaMax) supplemented with 10 % FBS. For passaging, medium was aspirated and replaced. Cells were detached using a cell scraper. Cells were counted using an automated cell counter (Thermo Fisher Scientific, Countess™) and respective Countess™ chamber slides. For counting, cell suspension was mixed with same volume trypan blue and 10 µL added to chamber. Back-calculation to cell number per mL was done by cell counter. Cells were seeded at 20,000 cells per well in a 96-well plate, or 60,000 cells per well in a 48-well plate, depending on format required for assay. 1.2.2 Cultivation of AMJ2-C11 AMJ2-C11, murine alveolar macrophages, are suspension cells. They were cultivated in DMEM (GlutaMax) supplemented with 5 % FBS and 5 mM HEPES. For subcultivation, 2-3 x10⁵ cells/mL were seeded in a new flask at least twice a week. Loosely adherent cells were detached by gently tapping the flask. For seeding, cells were centrifuged 5 min at ~262 x g and resuspended in fresh medium. Cells were counted using the Countess™ and seeded at a density of 25,000 cells/well in a 96-well plate, or 75,000 cells per well in a 48-well plate, depending on format required for assay. 1.2.3 Treatment In order to investigate GM-CSF pathway activation (target gene upregulation and STAT5 phosphorylation) upon treatment with recombinant GM-CSF, dilutions of recombinant murine GM- CSF (0.01, 0.25, 5, 100, 500 ng/mL) were prepared in respective cultivation medium.24 h after seeding, medium was aspirated and replaced with an equal volume of GM-CSF dilution (96-well plate: 100 µL / 48-well plate: 200 µL). Residual dilutions were stored at -80 °C for GM-CSF ELISA as nominal spikes. ^ Treatment Modification 01 In order to investigate possible downregulation of target genes upon incubation with monoclonal mGM-CSF-neutralizing antibody prior to short stimulus with recombinant mGM-CSF, RAW264.7 cells were seeded in four 48-well plates. RAW264.7 cells were cultivated in presence of antibody for one passage prior to seeding.24 h after seeding, anti-mGM-CSF antibody (Thermo Fisher Scientific, Cat. No. MM500C) was diluted to 3 µg/mL in cultivation medium for the controls (UT + mAb), or in medium supplemented with 0.25 ng/mL recombinant mGM-CSF (0.25 GM-CSF + mAb). Medium on RAW264.7 was aspirated and replaced with fresh respective medium (+/- mAb and +/- mGM-CSF).0.5 h after treatment, first samples (cells only) were collected. Medium on all other plates was replaced with fresh medium +/- mAb, but without recombinant GM-CSF. Further samples were collected after 1 h, 6 h, and 24 h, without further change of medium. ^ Treatment Modification 02 In order to investigate pSTAT5/STAT5 kinetics after transfection of mGM-CSF mRNA in RAW264.7 cells, cells were seeded in five 48-well plates.24 h after seeding cells were transfected with several doses of mGM-CSF mRNA (ETH048T65 – murine GM-CSF plasmid-based in vitro transcribed mRNA, 100% of N1-methyl-Pseudo-UTP) (SEQ ID NO:12) using Lipofectamine MessengerMax™. At 0.5 h, 1 h, 4 h, 6 h, and 24 h after transfection, supernatant and cells were sampled. Selected supernatants (doses and timepoints) were used for GM-CSF ELISA. Cells treated with doses of interest were analyzed for pSTAT5/STAT5 activation via western blot. Before sampling, cells were inspected in detail to determine possible toxicity effects at high mRNA doses. ^ Treatment for Modification 03 In order to investigate required dose of mGM-CSF mRNA versus recombinant mGM-CSF to overcome GM-CSF antibody-caused inhibition of STAT5 phosphorylation, RAW264.7 cells were treated with +/- mGM-CSF mRNA or recombinant GM-CSF as well as +/- neutralizing anti-mGM- CSF antibody (ThermoFisher Scientific, MM500C). Cells were seeded in T-175 flasks as for subcultivation on a Monday, using fresh regular RAW264.7 medium or medium supplemented with 3 µg/mL mAb. After 2 days, on Wednesday, cells were seeded at 6x10⁴ cells/well in eight 48- well plates +/- mAb.24 h after seeding, medium was replaced with fresh medium +/- mAb and +/- recombinant mGM-CSF, or medium was replaced with fresh medium +/- mAb before transfecting cells with mGM-CSF mRNA or scrambled mRNA as a control. Treatment with recombinant mGM-CSF or mRNA was incubated on cells until respective sampling timepoint. Cells were sampled after 1 h, 4 h, 6 h, and 24 h. 1.2.4 Sampling The supernatant of RAW264.7 cells was collected in storage plates and stored at -80 °C until GM- CSF ELISA analysis. Cells were washed once with PBS-/- and subsequently stored at -80 °C until lysis for qPCR or western blot. For sampling of AMJ2-C11 cells and supernatant, content of wells was collected in reaction tubes and centrifuged at 125 x g. The supernatant was collected for GM-CSF ELISA and stored at -80 °C. The cell pellet was washed once with PBS-/- and subsequently stored at -80 °C until lysis for qPCR or western blot. 1.2.5 qPCR of target genes SingleShot™ cell lysis buffer was prepared fresh and on ice according to Table 1. Lysis buffer was mixed thoroughly, centrifuged and was used within 2 h. Table 1 Lysis Buffer

Plates were taken out of -80 °C and 50 µL lysis buffer was added immediately in order to avoid loss of RNA due to degradation via RNases. The lysis buffer was incubated without agitation for 10 min at RT. Samples were processed within 20 min. Subsequently the cell lysate was transferred into a PCR plate. The plate was put into a thermal cycler with the following conditions: Table 2: Thermal cycler protocol for cell lysis

In general cell lysates can be stored for up to 12 months at -80 °C. For cDNA synthesis, plates with cell lysates were thawed on ice. All kit components, except iScript™ reverse transcriptase, were thawed on ice and mixed thoroughly and centrifuged briefly. cDNA synthesis was done using Oligo(dT) primers. The following components were added to a tube, whereby the iScript reverse transcriptase was added last: Table 3: Master Mix iScript™ Select cDNA Synthesis

16 µL Master Mix per well were pipetted in a new PCR plate before adding 4 µL cell lysate on top. The plate was sealed using a cover foil and mixed gently at 400 rpm before the plate was spun down briefly. cDNA synthesis was performed using a thermal cycle with the following protocol: Table 4: Thermal cycler protocol for cDNA synthesis

cDNA was stored at -20 °C until qPCR was performed. In order to prepare the master mix for qPCR, the following components were combined and vortexed briefly: Table 5: Master Mix qPCR TaqMan

Subsequently, 18 µL of TaqMan Master Mix were transferred to an optical 96-well qPCR reaction plate.2 µL cDNA template (cDNA and Nuclease free water) were added as shown in Table 6 to the optical 96-well qPCR reaction plate to obtain a final volume of 20 µL. The optical 96-well qPCR reaction plate was sealed with optical adhesive film and centrifuged for 2 min at max speed. Table 6: cDNA template preparation

Run mode “new experiment based on Roche Template” and “HydrolysisProbes” on LightCycler96 was selected. The following parameters to run a TaqMan assay were used: Table 7: Parameters for TaqMan

1.2.6 GM-CSF ELISA Supernatant of treated cells was analyzed using GM-CSF ELISA. A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, Cat. No.464718) was coated overnight at 4 °C with 2 µg/mL rat anti-mouse GM-CSF antibody (Abcam, Cat. No. ab210896) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, Cat. No. 37528) was added for blocking, using 50 µL per well and plate incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, a standard curve ranging from 0.6-10,000 pg/mL was prepared from recombinant murine GM-CSF (BioLegend, 576306). Standard curve and samples were added to the plate using 20 µL per well and the plate was incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 0.5 pg/mL HRP-coupled rabbit anti-mouse GM-CSF (Abcam, ab210896) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Then, the plate was washed 3x with PBST. Streptavidin-HRP solution (Abcam, ab210901) was diluted 1:500 and added to the plate using 20 µL per well. The plate was incubated 30 min at RT and 600 rpm. The plate was once more washed 3x with PBST. Lastly, 20 µL TMB (Merck, CL07-1000mL) were added to all wells and the plate was incubated 5 min on the bench top while protected from light. Reaction was stopped using 10 µL 1M H2SO⁴ and absorption measured at 450/650 nm with a microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using PBST. GM-CSF uptake by cells was calculated in relation to nominal spikes. 1.2.7 Western Blot Cells were lysed using 60 µL M-PER lysis buffer with protease inhibitor and DNase I Solution (23:1:1; M-Per:DNAse:cOmplete) per well (48-well format). For lysis, cells were incubated in lysis buffer for 30 min on ice. Before western blot, samples (60 µL) were mixed with 15 μL LDS sample buffer and 6 μL reducing agent and heated for 10 min at 70 °C. Reduced samples were stored at 20 °C. Bolt™ 4-12% SDS-PAGE combined with Trans-Blot® Turbo™ Transfer System (Bio-Rad) was used. SDS-PAGE was performed applying 200 V for approximately 60 min (PU.1) or 30 min (STAT5 / pSTAT5) and using MES running buffer to obtain optimal resolution in the lower range (PU.1) or MOPS buffer to obtain optimal resolution in the upper range (STAT5 and pSTAT5). Transfer was performed using the TransBlot® Turbo^TM Transfer System (Bio-Rad) for 30 min (standard program). After transfer, membranes were blocked in NET-gelatin at RT for 1 h. Primary antibody was diluted in NET-gelatin and the membrane was incubated over night at 4 °C. After three washes (10 min each) with blocking solution at RT, horseradish peroxidase-conjugated secondary antibody, diluted in NET-gelatin, was added at RT for 1 h. Subsequently, membranes were washed three times 10 min with NET-gelatin at room temperature (RT). STAT signals were visualized with Crescendo™ chemiluminescent substrate kit (membrane fully immersed for 2 min) and visualized using the ChemiDoc™ MP System (Bio-Rad). pSTAT signals were visualized using Forte chemiluminescent substrate kit. Housekeeper signals were visualized using Classico chemiluminescent substrate kit. To semi-quantify the signal, densitometry was performed using Image Lab™ software (Bio-Rad). 2 Results In order to investigate influence of GM-CSF on activation of GM-CSF signaling pathway and downstream targets, STAT5 activation via phosphorylation (first response in signaling cascade) and PU.1 upregulation were investigated using western Blot. Downstream targets were investigated using qPCR. 2.1 STAT5 activation in AMJ2-C11 cells upon treatment with recombinant GM-CSF (western blot) AMJ2-C11 cells were treated with 0.25 ng/mL or 500 ng/mL recombinant mGM-CSF and sampled after 0.5-24 h. Subsequently cells were lysed for western blot. STAT5 signals were visible for cells sampled at all timepoints, for both doses (Figure 1). Also untreated cells exhibited strong STAT5 bands (not phosphorylated). Overall, sufficiently adequate STAT5 levels could be verified in AMJ2-C11 cells. In order to analyze whether recombinant mGM-CSF was able to activate the STAT5 protein via phosphorylation in AMJ2-C11 cells, another blot of the same samples as in Figure 1 was stained with anti-pSTAT5 (phosphorylated STAT5) antibody (Figure 2). In AMJ2-C11 pSTAT5 signals could be observed upon treatment. Untreated cells did not exhibit any pSTAT5 signals. Slightly more intense bands 24 h after treatment seem to correlate with more intense housekeeper signals and were probably not induced by prolonged treatment. No obvious dose-dependent pSTAT5 signal differences could be observed. However, STAT5 was shown to be activated by recombinant mGM-CSF in AMJ2-C11 cells. 2.2 STAT5 activation in RAW264.7 cells upon treatment with recombinant GM-CSF (western blot) RAW264.7 cells were treated with 0.01 ng/mL or 100 ng/mL recombinant mGM-CSF and sampled after 0.5-24 h. Subsequently cells were lysed for western blot. STAT5 signals (Figure 3) were visible for cells sampled at all timepoints, for both doses. Also untreated cells exhibited STAT5 (not phosphorylated) bands. Overall, sufficiently adequate STAT5 levels could be verified in RAW264.7 cells. In order to analyze whether recombinant mGM-CSF was able to activate the STAT5 protein via phosphorylation in RAW264.7 cells, another blot of the same samples as in Figure 3 was stained with anti-pSTAT5 (phosphorylated STAT5) antibody (Figure 4). In RAW264.7 cells, pSTAT5 signals could be observed upon treatment. Untreated cells did not exhibit any pSTAT5 signals. No obvious dose-dependent (100 ng/mL vs. 0.01 ng/mL) pSTAT5 signal differences could be observed. However, STAT5 was shown to be activated by recombinant mGM-CSF in RAW264.7 cells. 2.3 PU.1 upregulation upon treatment with recombinant GM-CSF (western blot) RAW264.7 and AMJ2-C11 cells were treated with 0.25 ng/mL or 500 ng/mL recombinant mGM- CSF and sampled after 0.5-24 h. Cells were lysed for PU.1 western blot. In none of the two cell lines a GM-CSF-dependent increase in PU.1 signal could be observed. Increase in PU.1 signal after 24 h, that was also observed in untreated cells, was caused by continuous cell proliferation. This was indicated by respective housekeeper bands which were much more intense after 24 h (Figure 5, blots on the right). Thus, an influence of recombinant mGM-CSF on GM-CSF pathway downstream targets could not be shown on the PU.1 protein level. 2.4 Target gene upregulation upon treatment with recombinant GM-CSF (qPCR) RAW264.7 cells were treated with 0.01/0.25/5/100/500 ng/mL recombinant GM-CSF and sampled 0.5/1/6/24 h after treatment. Subsequently, cells were lysed for qPCR. As shown in Figures 6a and 6b, no upregulation (fold change >2) of target genes (Abcg1, Fcgr1, Fcgr2b, Fcgr3, Clec7a, PU.1) could be observed. AMJ2-C11 cells were treated with 0.01/0.25/5/100/500 ng/mL recombinant GM-CSF and sampled 0.5/1/6/24 h after treatment. Subsequently, cells were lysed for qPCR. As shown in Figure 7a-7c, no upregulation (fold change >2) of target genes (Abcg1, Fcgr1, Fcgr3, Clecl7a, PU.1) could be observed. No signal was obtained for Fcgr2b. 2.5 ELISA to investigate GM-CSF uptake. Lastly, as part of this experiment, GM-CSF uptake of cells was investigated. Supernatants containing recombinant mGM-CSF applied to cells was sampled after 0.5-24 h and analyzed via ELISA (Figures 8a and 8b). Uptake was evaluated by comparing measured GM-CSF levels to the nominal concentrations that were applied to cells. Overall, in RAW264.7 and AMJ2-C11 cells a trend towards a reduction of GM-CSF in supernatant over time could be observed. 2.6 Kinetic of STAT phosphorylation after treatment with rec GM-CSF 2.6.1 pSTAT5 western blot of Raw264.7 cells treated with GM-CSF +/- mAb. To investigate the possible downregulation of target genes upon incubation with monoclonal GM- CSF-neutralizing antibody prior to short stimulus with recombinant GM-CSF, RAW264.7 cells were incubated with 0.25 ng/mL rec. GM-CSF and +/- 3 µg/mL GM-CSF neutralizing antibody for 0.5 h. Subsequently, first cells were sampled. Others were placed in fresh medium without recombinant GM-CSF but again +/- antibody. Other cells were sampled 1/6/24 h after initial start of treatment and subsequently lysed for western blot shown in Figure 9. Untreated cells did not exhibit any pSTAT5 signals, independent of sampling-timepoint. RAW264.7 cells that were sampled after 0.5 h of incubation with recombinant GM-CSF but without antibody exhibited a relatively strong pSTAT5 band.0.5 h later (Sampling-timepoint: 1 h, duration of incubation with recombinant GM-CSF: 0.5 h) the pSTAT5 signal was still there, but already much weaker.6 h after initial treatment (duration of incubation with recombinant GM-CSF: 0.5 h), the pSTAT5 signal was barely visible and after 24 h there was absolutely no pSTAT5 signal anymore. This became even more obvious when analyzing the densitometry (Figure 10). At no timepoint a pSTAT5 band was visible in cells that were incubated in presence of GM-CSF-neutralizing antibody. Thus, 0.25 ng/mL recombinant GM-CSF were not sufficient to overcome 3 µg/mL monoclonal GM-CSF- neutralizing antibody. As soon as no antibody was present, recombinant GM-CSF induced STAT5 phosphorylation, already visible at timepoints as early as 0.5 h. STAT5 phosphorylation transiently decreased as soon as recombinant GM-CSF was removed. 2.6.2 qPCR of target genes in RAW264.7 cells treated with GM-CSF +/- mAb. RAW264.7 cells were incubated with 0.25 ng/mL recombinant GM-CSF and +/- 3 µg/mL GM-CSF neutralizing antibody for 0.5 h. Subsequently, first cells were sampled. Others were placed in fresh medium without recombinant GM-CSF but again with or without antibody in order to investigate the influence of a short GM-CSF stimulus in the presence of GM-CSF-neutralizing antibody. After medium exchange, the cells were sampled 1/6/24 h post initial start of treatment and subsequently lysed for qPCR shown in Figures 11a and 11b. Fold changes were calculated by normalizing to untreated cells without antibody. After Treatment with recombinant GM-CSF no activation of the downstream targets could be detected. 2.7 pSTAT5/STAT5 kinetics after transfection of GM-CSF mRNA In order to investigate pSTAT5/STAT5 kinetics after transfection of GM-CSF mRNA, RAW264.7 cells were transfected with 47-750 ng/well (94-1500 ng/cm²) of GM-CSF mRNA in a 48-well plate format. 0.5/1/4/6/24 h after transfection, supernatants and cells were sampled. Supernatants were analyzed via GM-CSF ELISA and quantified (Figures 12 and 13). Cells were lysed for pSTAT5 western blot (Figure 14). The GM-CSF ELISA showed that as early as 4 h after transfection, GM-CSF levels >1000 pg/mL have been detected, and thus already much higher levels have been achieved with the GM-CSF mRNA than with recombinant GM-CSF used in previous experiments with GM-CSF-neutralizing antibody. GM-CSF could be measured in supernatant of cells transfected with any dose. Cells transfected with 750/188/47 ng/well were used for western blot. Blots (Figure 14) clearly show that doses lower than 750 ng induce pSTAT5 signals the earliest 1 h after transfection. Cells transfected with 750 ng already exhibit a signal 0.5 h after transfection. Thus, as ELISA was not able to detect any GM-CSF levels below lower limit of quantification in supernatants collected 0.5 h after transfection, already GM-CSF levels below lower limit of quantification are sufficient to induce pSTAT5 signal in RAW264.7 within 0.5 h after transfection. The western blot shows that once a pSTAT5 band is visible, the signal does not decrease. Thus, STAT5 phosphorylation is not transient, as long as GM-CSF is constantly present. The reduction in pSTAT5 signal observed in blot of cells transfected with 750 ng, might be caused by generic mRNA cytotoxicity, as RAW264.7 react very sensitive to higher mRNA doses. 2.8 Comparison between GM-CSF-mRNA and rec GM-CSF In order to investigate the required dose of GM-CSF mRNA 100 % N1-Methylpseudouridine modified (SEQ ID NO:12) versus recombinant GM-CSF to overcome GM-CSF antibody-caused inhibition of STAT5 phosphorylation, RAW264.7 cells were treated with or without mGM-CSF mRNA or recombinant GM-CSF as well as with or without neutralizing anti-mGM-CSF antibody. Cells were sampled after 1 h, 4 h, 6 h, and 24 h. western blot showed, that already 5 ng/mL recombinant GM-CSF was sufficient to induce STAT5 phosphorylation in presence of monoclonal neutralizing antibody (Figure 15). Also, all chosen doses of GM-CSF mRNA (6/47/375 ng/cm²) were sufficient to induce STAT5 phosphorylation in presence of monoclonal neutralizing antibody. 1 h after transfection, pSTAT5 signals in cells transfected with 6 or 47 ng/cm² mRNA were weaker than in cells transfected with 375 ng/cm². Also, 1 h after transfection, the inhibitory effect of the neutralizing antibody on STAT5 phosphorylation was still visible. pSTAT5 bands of cells +/- mAb converged already 4 h after transfection. Here, no obvious difference between bands +/- mAb was visible anymore, except for cells transfected with 6 ng/cm². 3 Discussion and Conclusion 3.1 Activation of GM-CSF pathway GM-CSF pathway downstream target gene upregulation upon treatment with recombinant GM- CSF could not be observed using qPCR or western blot in RAW264.7 or AMJ2-C11 cells. GM- CSF pathway upstream target protein STAT5 activation via phosphorylation upon treatment with recombinant GM-CSF or GM-CSF mRNA could be observed in RAW264.7 and AMJ2-C11 cells. Phosphorylated STAT5 signal could be observed using western blot as long as recombinant GM- CSF was present. 3.2 Kinetics of STAT5 activation using recombinant GM-CSF A short stimulus of a low dose of recombinant GM-CSF (30 min 250 pg/mL) was sufficient to induce phosphorylation of STAT5 in RAW264.7 cells, shown using western blot, without the presence of monoclonal GM-CSF-neutralizing antibody. As soon as recombinant GM-CSF was removed, pSTAT5 signal decreased over time until not further detectable 6 h after removal. In presence of GM-CSF-neutralizing antibody, 250 pg/mL recombinant GM-CSF was not sufficient to induce STAT5 phosphorylation. 3.3 Kinetics of STAT5 activation using GM-CSF mRNA Transfection of RAW264.7 cells with GM-CSF mRNA was shown to induce phosphorylation of STAT5, detectable via western blot, already at doses that yielded GM-CSF levels not detectable in ELISA (1 h after 47 ng/cm²). Once a pSTAT5 signal was observed in western blot, signal strength did not increase further over time or dose. Hence, maximum pSTAT5 levels were rapidly reached as soon as 1 h after transfection using doses ≤188 ng/cm² and as soon as 30 min after transfection using 750 ng/cm². 3.4 Kinetics of STAT5 activation in presence of monoclonal GM-CSF-neutralizing antibody A dose of 5000 pg/mL recombinant GM-CSF was sufficient to induce STAT5 phosphorylation in RAW264.7 cells, shown using western blot, in presence of monoclonal GM-CSF neutralizing antibody as early as 1 h after application (earliest timepoint investigated). GM-CSF mRNA dose of 6 ng/cm² was also sufficient to induce STAT5 phosphorylation in RAW264.7 cells. However, a full pSTAT5 signal strength in the presence of antibody was reached at timepoints later than 1 h (subsequent investigated timepoint: 4 h). This is the time needed to express GM-CSF from the mmRNA. The results show that GM-CSF expression from mRNA is a fast process and expression effect of the expressed mRNA can be observed already 4 hours after mRNA delivery. 3.5 Summary In RAW264.7 and AMJ2-C11 cells, the GM-CSF pathway can be activated via recombinant GM- CSF or GM-CSF mRNA. Under our conditions proximal GM-CSF pathway activation could be detected, using western blot to show activation of STAT5 via phosphorylation upon treatment with GM-CSF. Evidence of pathway activation via upregulation of downstream targets via pSTAT as a “proximal” marker for activation of downstream targets could not be detected using qPCR or western blot. Herein it is shown that recombinant GM-CSF and GM-CSF mRNA are both able to overcome inhibition of STAT5 activation (the primary marker for the GM-CSF pathway activation in vitro) in the presence of a monoclonal GM-CSF neutralizing antibody at the doses discussed above. Thus, the invention’s mRNA provides a fast and excellent activation of STAT5 and a long- lasting effect for at least 24 hours, showing a measurable downstream effect and as early as 4 hours after mRNA delivery.. Example 2 Evaluation of GM-CSF downstream targets using TaqMan Probes The aim of this experiment was to develop a qPCR method for the detection of GM-CSF downstream targets. Therefore, TaqMan probes for 8 different downstream targets (Pu.1, Pparg, Abcg1, Fcgr1, Fcgr2b, Fcgr3, Clec7a, Fcgr4) were evaluated. As control, cDNA from RAW 264.7 cells treated with recombinant mouse GM-CSF protein was used for qPCR to assess downstream target activation. RAW 264.7 cells were treated for 24 h with mouse GM-CSF mRNA (SEQ ID NO:12, 30 % I5U/ 3% I5C, 10 ng/96-well/per well) or recombinant GM-CSF protein (40.000 pg/mL) before cells were lysed, total RNA was extracted and reversed transcribed to cDNA. qPCR was conducted using TaqMan probes for the respective GM-CSF downstream targets. In the murine cell line RAW 264.7 it could be shown that 6 out of 8 downstream targets were upregulated 24 h after transfection with modified mRNA coding for murine GM-CSF. Upregulation was similar to upregulation induced by recombinant mGM-CSF for Fcgr1 and Fcgr3. For Pu.1, Abcg1, Fcgr2b and Celc7a upregulation after treatment with modified mRNA ( 30 % I5U/ 3% I5C) was higher compared to treatment with recombinant protein (1.5-4 fold). Abbreviations & Definitions

1 Materials and Methods 1.1 Materials

1.2 Methods For the evaluation of GM-CSF downstream target activation after transfection with murine GM- CSF mRNA (PCR-based transcript, modified mRNA (30% I5U/3% I5C modified, SEQ ID NO:33) or stimulation with recombinant mGM-CSF a qPCR was conducted using TaqMan probes system. 1.2.1 Cultivation and seeding Mouse macrophage cell line (RAW 264.7) was cultivated in high glucose DMEM supplemented with 10 % FBS. To detach cells for seeding cell scarpers were used. Therefore, old medium was aspirated, and 10 mL fresh medium (for T175 flask) added. Cells were carefully scraped off the flasks, transferred to a 50 mL falcon and counted using a Countess™ Cell counting chamber and 2x10^4 cells were seeded per 96-well. 1.2.2 Treatment To induce GM-CSF target genes, cells were treated with 10 ng/96-well mGM-CSF mRNA (30% I5U/3% I5C modified) (SEQ ID NO:33) or with murine recombinant GM-CSF protein (40.000 pg/mL) for 24 h. 1.2.3 Transfection and sampling Cells were seeded in their respective density 24 h before treatment. Approx.24 h after seeding fresh medium was added to each well (100 µL per 96-well). All mRNAs were transfected using Lipofectamine® MessengerMAX™ in an RNA to Lipofectamine ratio of 1:1.5 (w/v). All RNAs have a stock concentration of 1 mg/mL. For lipoplex formation mRNA was diluted in dH₂O. Lipofectamine® MessengerMAX™ was diluted in medium without serum and without P/S and mixed by pipetting. After incubation of 10 min at RT, the RNA solution was added to the Lipofectamine® MessengerMAX™ solution, mixed and incubated for another 5 min at RT. Afterwards, the lipoplex solution was added to the wells. After 24 h treatment with murine GM-CSF mRNA (SEQ ID NO:33, 30% I5U/3% I5C modified, 10 ng/96-well) or recombinant GM-CSF (40.000 pg/mL) cells were washed once with cold DPBS-/- and after aspirating the DPBS, the plate was stored at -80°C. 1.2.4. Cell Lysis using the SingleShot™ Cell Lysis Kit Preparation of the SingleShot™ cell lysis buffer was done according to Table 8. Preparation was done always fresh and on ice. The lysis buffer was mixed thoroughly and centrifuged and had to be used within 2 h. Table 8 Lysis Buffer

For cell lysis the cell culture medium was aspirated, and cells were washed with 300 µL D-PBS per well before the plates were frozen at -80 °C.50 µL lysis buffer for RNA isolation was added per well and incubated without agitation for 10 min at RT, without mixing. Samples were processed within 20 min. Subsequently the cell lysate was transferred to a PCR plate. Protein and DNA was digested using the program “BioDNA” with the following conditions: Table 9: Thermal cycler protocol for cell lysis

The cell lysates were stored at -80 °C. 1.2.5 cDNA Synthesis using iScript™ Select cDNA Synthesis Kit The plates with the cell lysates were thawed on ice. All kit components, except iScript™ reverse transcriptase, were thawed on ice and mixed thoroughly and centrifuged briefly. cDNA synthesis was done using Oligo(dT) primers. The following components were added to a 2 mL tube, where the iScript reverse transcriptase was added after the other components. Table 10: Master Mix iScript™ Select cDNA Synthesis.

4 µL of the cell lysate were pipetted in a new PCR plate using a multi-channel pipet, before adding 16 µL of the master mix on top. The plate was sealed using a cover foil and mixed gently at 400 rpm before the plate was spun down briefly. cDNA synthesis was performed using a thermal cycle with following protocol (“ISCRIPT2”). Table 11: Thermal cycler protocol for cDNA synthesis

cDNA was stored at -20 °C until qPCR was performed. 1.2.6 qPCR using TaqMan probes for mouse constructs The following components were combined (see Table 12) and vortexed briefly. To bring the reaction mix to the bottom of the tube and to eliminate air bubbles the mix was briefly centrifuged. 18 µL of TaqMan Master Mix were transferred to an optical 96-well qPCR reaction plate.2 µL cDNA template (cDNA and Nuclease free water, see Table 13) were added as shown in Table 13 to the optical 96-well qPCR reaction plate to obtain a final volume of 20 µL. The optical 96-well qPCR reaction plate was sealed with optical adhesive film and briefly centrifuged. Table 12: Master Mix qPCR TaqMan

Table 13: cDNA template preparation

Following parameters were used to run a TaqMan assay: Table 14: Parameters for TaqMan

2 Results To assess downstream target activation in the GM-CSF pathway, a murine cell line RAW 264.7 was used. Downstream target activation upon transfection with modified mRNA ETH048T65 (SEQ ID NO:12, murine GM-CSF, obtained by transcription of a linearized plasmid, modified with 100% N1-methyl-pseudouridine) was determined using qPCR for Pu.1, Abcg1, Fcgr1, Fcgr2b, Fcgr3, Celc7a, Pprg and Fcgr4 with EGFP as transfection control. As control for the target gene activation, recombinant murine GM-CSF protein was used. Cells treated with recombinant protein were normalized to untreated cells. Transfection with modified mRNA was done using 10ng/well/ in 96-well for 24 h and treatment with recombinant protein was done using 40.000 pg/mL for 24 h before analysis. GAPDH and Rplp0 were used as reference genes for qPCR. Downstream target activation after 24 h of treatment was observed for Pu.1, Abcg1, Fcgr1, Fcgr2b, Fcgr3 and Celc7a. No target gene activation was found for Pprg and Fcgr4. After evaluating the reference genes, it was found that the reference gene GAPDH was upregulated already by the transfection with mGM-CSF mRNA per se, but not with the treatment with recombinant protein. Thus, the values were recalculated using only Rplp0 as reference gene to obtain a more accurate result. After recalculation, using only Rplp0 as reference gene an upregulation of target genes could be confirmed (1.5-4-fold). 3 Discussion and Conclusion In the murine cell line RAW 264.7 it could be shown that 6 downstream targets were upregulated 24 h after transfection with modified mRNA coding for murine GM-CSF (1.5-4-fold). Upregulation was similar to upregulation induced by recombinant protein for Fcgr1 and Fcgr3. For Pu.1, Abcg1, Fcgr2b and Celc7a upregulation after treatment with 100% N1-Methylpseudouridine modified mRNA (ETH048T65, SEQ ID NO:12) was higher compared to treatment with recombinant protein. Thus, the mRNA of the present invention results in GM-CSF expression and thereby provides an effective activation of GM-CSF downstream genes (particularly of the primary/proximal marker STAT5), and in the case of Fcgr2b and Celc7a provides a higher upregulation than recombinant GM-CSF. Example 3 Low dose titration of GM-CSF mRNA in RAW264.7 cells The aim of this experiment was to investigate GM-CSF protein yield in RAW264.7 cells after transfection of low mRNA doses (SEQ ID NO:12 modified with 100 % N1-Methylpseudouridine). The aim was to find the dose that will yield a GM-CSF concentration just above the lower limit of quantification of the GM-CSF ELISA (50 pg/mL). This is required in order to emulate the GM-CSF levels in epithelial lining fluid (ELF) within lungs of healthy individuals and that of GM-CSF deficiency diseases such as PAP patients in vitro, which range somewhere from ≤ ~10 to ≥ ~100 pg/mL. It could be shown that RAW264.7 cells can be transfected with GM-CSF mRNA specifically to yield 100 or 1,000 pg/mL GM-CSF in supernatant after 1, 4, 6, or 24 h. Yields <50 pg/mL could not be quantified, as they were below the lower limit of quantification (See Figure 18) 1 Materials and Methods 1.2 Materials Material Supplier Cat no.

Material Supplier Cat no.

1.3 Methods 1.3.1 Cultivation of RAW 264.7 The murine macrophage cell line RAW 264.7 was cultivated in DMEM (GlutaMax) supplemented with 10 % FBS. For passaging, non-adherent cells are collected, medium was aspirated and replaced. Cells were detached using a cell scraper, combined with non-adherent fraction, and split as required. For seeding, cells were centrifuged at ~262 x g and subsequently resuspended in fresh medium. Cells were counted using the Countess Cell Counter and seeded at 2x10⁴ cells per well in 4x 96-well plate. 1.3.2 Transfection and harvest 24 h after seeding, cells were transfected with murine GM-CSF ETH048T65 (murine GM-CSF, codon optimized, IVT from linearized plasmid, 100% of N1-methyl-Pseudo-UTP, SEQ ID NO:12) using Lipofectamine MessengerMax™. mRNA to Lipofectamine ratio is 1:1.5. Murine GM-CSF mRNA ETH048T65 was used. Employed doses and layout for transfection are shown in Table 15. Total transfection volume within well is 125 µL. Subsequently, 1 h, 4 h, 6 h, and 24 h after transfection, supernatant is collected in a storage plate and stored at 4°C, if ELISA is conducted immediately after last sample collection, or otherwise at -80 °C. Table 15: Transfection layout (ng/well)

Transfections were done in a 96-well format. The volume per well is ~0.3 cm². To translate the amount of RNA in Table 15 to ng/cm², the amount of RNA is multiplied by 3 (each well is ~0.3 cm²). 1.3.3 GM-CSF ELISA A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, 464718) was coated overnight at 4 °C with 2 µg/mL rat anti-mouse GM-CSF antibody (Abcam, ab210896) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, 37528) was added for blocking, using 50 µL per well and plate incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, a standard curve ranging from 0.6-10,000 pg/mL was prepared from recombinant murine GM-CSF (BioLegend, 576306). Samples to generate a standard curve and measurement samples were added to the plate using 20 µL per well and incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 0.5 pg/mL HRP-coupled rabbit anti-mouse GM-CSF (Abcam, ab210896) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Then, the plate was washed 3x with PBST. Streptavidin-HRP solution (Abcam, ab210901) was diluted 1:500 and added to the plate using 20 µL per well. The plate was incubated 30 min at RT and 600 rpm. The plate was once more washed 3x with PBST. Lastly, 20 µL TMB (Merck, CL07- 1000mL) were added to all wells and the plate was incubated 5 min on the bench top while protected from light. The reaction was stopped using 10 µL 1M H2SO4 and absorption was measured at 450/650 nm with a microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using PBST. 2 Results For all four time points and both transfected mRNA titrations, clear dose-dependent GM-CSF yields were measured in RAW264.7 supernatant (Figure 18). GM-CSF yields of 100 pg/mL or 1000 pg/mL GM-CSF were obtained using doses shown in Table 16. Yields <50 pg/mL could not be quantified, as they were <LLOQ. 3 Discussion and Conclusion RAW264.7 cells can be transfected with GM-CSF mRNA in selected doses in order to yield 100 or 1000 pg/mL GM-CSF, if the supernatant is harvested after 1, 4, 6, or 24 h. Required doses are listed in Table 16. Yields <50 pg/mL could not be quantified, as they were <LLOQ. Upon transfection of RAW264.7 murine macrophages with GM-CSF mRNA concentrations that reflect the physiological concentrations of GM-CSF in the airway surface lining fluid (i.e., between 100 – 1000 pg/mL) can be achieved. At 300ng mRNA/cm² the physiological concentration is reached as early as 1h post transfection, a dose of 3ng/cm² yields physiological concentration 6h post transfection and a concentration as low as 0.3 ng/cm² is sufficient to result in a GM-CSF concentration in the physiological range after 24h. Table 16: mRNA doses required to obtain 100 or 1000 pg/mL in RAW264.7 supernatant at time point of harvest.

Example 4 Effect of GM-CSF on phosphorylation of STAT5 in the presence of a GM-CSF neutralizing antibody The aim of this study was to investigate the effect of recombinant GM-CSF/GM-CSF mRNA on the activation of the GM-CSF pathway in the murine macrophage cell line RAW264.7 in the presence of a GM-CSF-neutralizing antibody. Activation of GM-CSF pathway was defined by phosphorylation of STAT5. Herein it is shown that GM-CSF expressed by RAW264.7 cells transfected with GM-CSF-coding mRNA (SEQ ID NO:33, modified with 30 % I5U/ 3% I5C) induces STAT5 phosphorylation via autocrine stimulation more effectively than recombinant GM-CSF added to the supernatant. The same GM-CSF concentrations obtained after transfection of mRNA, as were added using recombinant protein, induce stronger STAT5 phosphorylation (Figure 23). In contrast to recombinant GM-CSF added to the supernatant, GM-CSF expressed by the macrophages via the administered mRNA was not affected by polyclonal GM-CSF-neutralizing antibodies (Figure 23). While the STAT5-activating effect of recombinant GM-CSF was impaired as soon as it was removed from cells 4 h after treatment, the effect of GM-CSF mRNA surprisingly remained unaltered. This highlights the overall advantage of GM-CSF mRNA in contrast to recombinant GM-CSF. mRNA is able to induce an auto-stimulatory GM-CSF signaling loop, and, once taken up by cells, is not subjected to a fast turnover as is the case for the recombinant GM-CSF protein. Thus, herein it is shown that GM-CSF mRNA can exert its STAT5-activating effect longer and more effectively. Abbreviations & Definitions ^ Abbreviation ^ Description

^ TRIS ^ Tris(hydroxymethyl)aminomethane Materials and Methods Materials

1.2 Methods 1.2.1 Subcultivation and seeding of murine macrophage cell line RAW264.7 The murine macrophage cell line RAW 264.7 was cultivated in DMEM (GlutaMax™) supplemented with 10 % FBS. For passaging, medium was aspirated and replaced. Cells were detached using a cell scraper. For seeding, cells were collected as described, centrifuged at 262 x g and subsequently resuspended in fresh medium. Cells were counted using an automated cell counter (Thermo Fisher Scientific, Countess™) and respective Countess™ chamber slides. For counting, cell suspension was mixed with the same volume trypan blue and 10 µL added to chamber. Back-calculation to cell number per mL was done by cell counter. Cells were seeded at 6x10⁴ cells per well in a 48-well plate. 1.2.2 Treatment and harvest 1.2.2.1 Neutralizing effect of monoclonal vs. polyclonal GM-CSF-neutralizing antibody 24 h after seeding in a 48-well format, supernatant of RAW264.7 cells was aspirated. Cells were treated with a combination of recombinant mGM-CSF (1, 10, 100, 1000 pg/mL) and 5 µg/mL monoclonal or 5 µg/mL polyclonal GM-CSF neutralizing antibody within a volume of 200 µL/well in a 48-well format. As a positive control, cells treated with 10,000 pg/mL recombinant mGM-CSF were included in this experiment. Cells were incubated with treatments for 4 h. Subsequently, supernatant was aspirated, and cells were washed once using PBS -/-. The plate with cells was stored at -80 °C until western blot analysis. 1.2.2.2 Effects of recombinant GM-CSF vs. GM-CSF modified mRNA in presence of polyclonal GM-CSF neutralizing antibody. 24 h after seeding in a 48-well format, supernatant of RAW264.7 cells was aspirated. Cells were either transfected with 0.3-30 ng/cm² mGM-CSF mRNA (ETH048T65, SEQ ID NO:12, plasmid- based in-vitro transcribed GM-GSF, 100% N1-methyl-Pseudo-UTP mRNA) using Lipofectamine and an mRNA:Lipofectamine ratio of 1:1.5, or treated with 10, 100, or 1000 pg/mL recombinant mGM-CSF. As a negative control for western blot, cells transfected with non-coding Stop mRNA, were included in this experiment. Simultaneous with recombinant GM-CSF and transfection, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing polyclonal antibody. Technical duplicates were prepared. Both replicates were used for ELISA, only one was used for western blot. Supernatants and cells were harvested 4 h, 6 h, and 24 h after treatments. After the supernatant had been harvested, cells were washed once using PBS-/-. The plate with cells and supernatant was stored at -80 °C until analysis with western blot and ELISA, respectively. This experiment was conducted in total three times (n=3). Results are shown in Figure 21. 1.2.2.3 Effects of recombinant GM-CSF vs GM-CSF modified mRNA in presence of polyclonal GM-CSF-neutralizing antibody but after exchange of medium. 24 h after seeding in a 48-well format, the supernatant of RAW264.7 cells was aspirated. Cells were either transfected with 0.3-30 ng/cm² mGM-CSF mRNA (ETH048T65, SEQ ID NO:12, plasmid-based in-vitro transcribed murine GM-CSF 100% N1-methyl-Pseudo-UTP) using Lipofectamine and an mRNA:Lipofectamine ratio of 1:1.5, or treated with 10, 100, or 1000 pg/mL recombinant mGM-CSF. As a negative control for western blot, cells transfected with non-coding Stop mRNA, were included in this experiment. Simultaneously with recombinant GM-CSF and transfection solution, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing polyclonal antibody. Technical duplicates were prepared. Both replicates were used for ELISA, only one was used for western blot. 4 h after treatments, medium was aspirated and replaced with fresh medium supplemented with 5 µg/mL polyclonal GM-CSF-neutralizing antibody. Supernatants and cells were harvested 4 h, 6 h, and 24 h after initial treatments. After supernatant had been harvested, cells were washed once using PBS-/-. The plate with cells and supernatant was stored at -80 °C until analysis with western blot and ELISA, respectively. This experiment was conducted twice (n=2). Results are shown in Figure 23 and 24. 1.2.3 GM-CSF ELISA Cell supernatant was analyzed via GM-CSF ELISA. A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, 464718), which was coated over night at 4 °C with 2 µg/mL rat anti-mouse GM- CSF antibody (Abcam, ab210896) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, 37528) was added for blocking, using 50 µL per well and the plate incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, standard curve ranging from 0.6-10,000 pg/mL was prepared from recombinant murine GM-CSF (BioLegend, 576306). Standard curve and samples were added to the plate using 20 µL per well and incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 0.5 pg/mL HRP-coupled rabbit anti-mouse GM- CSF (Abcam, ab210896) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Then, the plate was washed 3x with PBST. Streptavidin-HRP solution (Abcam, ab210901) was diluted 1:500 and added to the plate using 20 µL per well. The plate was incubated 30 min at RT and 600 rpm. The plate was once more washed with 3x with PBST. Lastly, 20 µL TMB (Merck, CL07-1000mL) were added to all wells and the plate was incubated 5 min on bench top while protected from light. The reaction was stopped using 10 µL 1M H2SO4 and absorption was measured at 450/650 nm with a microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using PBST. 1.2.4 pSTAT5 western blot a) Sample preparation Cells were lysed using 60 µL M-PER lysis buffer per well (48-well format) with protease inhibitor and DNase I Solution (23:1:1; M-Per:DNAse:cOmplete) and incubated on ice for 30 minutes. Before western blot, each sample was mixed with 15 μL LDS sample buffer and 6 μL reducing agent in the well and heated for 10 min at 70 °C and 350 rpm. b) SDS-PAGE and Blotting Method For SDS-PAGE, Bolt™ 4-12% Bis-Tris Plus was used. SDS-PAGE was performed by applying 200 V for 28 min and using MOPS running buffer to obtain optimal resolution in the upper range. Transfer was performed using the TransBlot® Turbo^TM Transfer System (Bio-Rad) for 30 min. c) Blocking and Antibody Incubation After transfer, membranes were blocked at room temperature for 1 h using 1x NET-Gelatin (NaCl- EDTA-Triton). NET-Gelatin was prepared. Membranes were incubated agitating overnight at 4 °C with the primary, unconjugated antibodies (anti-pSTAT5 or anti-GAPDH as housekeeper). After three washes (10 min each) with blocking solution at RT, horseradish peroxidase-conjugated secondary antibody was added at RT for 1 h. Again, membranes were washed 3 x 10 min with blocking solution at RT before signal development. d) Chemiluminescent Signal Development Signals were visualized with a chemiluminescent substrate kit. For pSTAT5 membranes, Merck Luminata™ Forte Western HRP substrate was used. For GAPDH membranes, Merck Luminata™ Classico was used. Membranes were incubated 2 min in ~5 mL substrate and subsequently visualized using the ChemiDoc™ MP System (Bio-Rad). To semi-quantify the signal, densitometry was performed using the Image Lab™ software (Bio-Rad). 2. Results 2.1 Neutralizing effect of monoclonal vs. polyclonal GM-CSF-neutralizing antibody The aim was to compare the neutralizing effect of a monoclonal GM-CSF-neutralizing antibody to that of a polyclonal GM-CSF-neutralizing antibody. A neutralization effect was aimed to be analyzed by visualization of pSTAT5 levels in cells via western blot. STAT5 phosphorylation is induced by GM-CSF. Vice versa, STAT5 phosphorylation was hypothesized to be impaired by a GM-CSF-neutralizing antibody. For this purpose, RAW264.7 cells were seeded in a 48-well format at 60,000 cells/well.24 h after seeding, medium was removed and cells were supplied with fresh medium supplemented with 5 µg/mL neutralizing antibody (monoclonal or polyclonal) and/or 1, 10, 100, or 1000 pg/mL recombinant murine GM-CSF. GM-CSF doses of 1-1000 pg/mL were chosen specifically to represent the range of GM-CSF levels that are present in lungs of healthy individuals and that of PAP patients (Carraway et al., Am J Respir Crit Care Med., Vol 161. Pp 1294-1299, 2000). Antibody concentration of 5 µg/mL was chosen based on antibody concentrations found in PAP patients (Sakagami et al., Am J Respir Crit Care Med., 182(1), 49-61, 2010). Cells were harvested for western blot 4 h after treatment. This experiment shows that without any GM-CSF-neutralizing antibody, already 10 pg/mL recombinant GM-CSF induced STAT5 phosphorylation in RAW264.7 cells (Figure 19, arrow 1). In cells, however, that had been treated with polyclonal antibody (pAb), not even 1000 pg/mL recombinant GM-CSF can overcome the neutralizing effect of the antibody (Figure 19, arrow 2). In cells that had been treated with monoclonal antibody (mAb), 1000 pg/mL recombinant GM- CSF induces STAT5 phosphorylation, whereas 100 pg/mL do not (Figure 19, arrow 3). Thus, it is shown that polyclonal GM-CSF-neutralizing antibody inhibits STAT5 phosphorylation more efficiently in RAW264.7 cells than monoclonal GM-CSF neutralizing antibody. To properly simulate the strong GM-CSF-neutralizing antibody environment in PAP patients, the polyclonal antibody is used for all subsequent experiments. 2.2 Effects of recombinant GM-CSF vs GM-CSF modified mRNA in presence of polyclonal GM- CSF-neutralizing antibody. The first experiment of this study showed that 1000 pg/mL recombinant GM-CSF was not sufficient to trigger STAT5 phosphorylation in RAW264.7 cells in the presence of polyclonal GM- CSF-neutralizing antibody. Thus, the aim was now to investigate whether a GM-CSF mRNA could be proven superior to recombinant GM-CSF and induce STAT5 phosphorylation even in presence of a neutralizing antibody. For this purpose, RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding, cells were either transfected with 0.3-300 ng/cm² GM-CSF mRNA ETH048T65 (SEQ ID NO:12, murine GMCSF, plasmid-based, 100% N1-methyl-Pseudo-UTP) (or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. A dose range for the transfection was chosen based on known transfection efficiency of GM-CSF mRNA in RAW264.7 cells, investigated in previous studies. It was aimed to hit a yield of 1000 pg/mL in cells without neutralizing antibody 4 h after transfection with 30 ng/cm² and 10-times less with each respective lower dose. Two higher doses were included to make sure that the neutralizing effect of the antibody could certainly be overcome. Simultaneously with recombinant GM-CSF and transfection, the cells were also supplemented with 5 µg/mL polyclonal GM-CSF-neutralizing antibody. Supernatants and cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted in total three times (n=3). GM-CSF ELISA confirmed predicted GM-CSF yields in supernatant (Figure 20) of 1000 pg/mL GM-CSF with 30 ng/cm² mRNA, 100 pg/mL GM-CSF were obtained with 3 ng/cm² mRNA, and ~10 pg/mL GM-CSF (<LLOQ) were obtained with 0.3 ng/cm² mRNA at 4 h after transfection. For second and third repetition of this experiment, both high doses (150 ng/cm² and 300 ng/cm²) were not employed any further, as lower doses proved sufficient to induce STAT5 phosphorylation. Next, pSTAT5 western blots using cell lysates were conducted. pSTAT5 was semi-quantified via densitometry (Figure 21). It could be shown that in contrast to recombinant GM-CSF, which again was not able to overcome inhibition of STAT5 phosphorylation caused by GM-CSF-neutralizing antibody, GM-CSF mRNA did indeed induce STAT5 phosphorylation already 4 h after treatments in presence of neutralizing antibody even at doses that were previously shown to yield <1000 pg/mL GM-CSF without neutralizing antibody at this time point (Figure 20). As shown in Figure 21, no distinct pSTAT5 levels above background level (Mean _{(UT 4-24 h)}+2*SD_{(UT 4-24 h)}) were obtained 4 h and 6 h after addition of recombinant GM-CSF in presence of GM-CSF-neutralizing antibody. In the absence of the neutralizing antibody, recombinant GM-CSF was able to induce dose- dependent pSTAT5 levels. Without the presence of the antibody, GM-CSF mRNA induced what appeared to be maximum pSTAT5 levels already 4 h after treatment even with the lowest dose of only 0.3 ng/cm², which had been shown to equal ~10 pg/mL GM-CSF at this time point after treatment. As soon as neutralizing antibody was present in addition to GM-CSF mRNA, it was observed that STAT5 phosphorylation still did occur, but now in a distinctly dose-dependent manner, as was observed for recombinant GM-CSF without antibody.24 h after treatment and without antibody, both in cells treated with recombinant GM-CSF and in cells transfected with GM- CSF mRNA, pSTAT5 levels were reduced compared to earlier time points. However, while pSTAT5 levels after 10 pg/mL and 100 pg/mL of recombinant GM-CSF were back to background level intensity, pSTAT5 levels remained distinctly elevated in cells transfected with any mRNA dose. Thus, in the presence of polyclonal GM-CSF-neutralizing antibody, GM-CSF mRNA was even more efficient in inducing STAT5 phosphorylation than recombinant GM-CSF was without the neutralizing antibody. GM-CSF mRNA was not only shown to be effective in overcoming inhibition of STAT5 phosphorylation caused by GM-CSF-neutralizing antibody, but was also shown to induce phosphorylation more efficiently overall than recombinant GM-CSF. This conclusion could also be drawn when relative pSTAT5 abundance, semi-quantified via densitometry, was depicted in relation to GM-CSF levels quantified in RAW264.7 supernatants at respective time points (Figure 22). The relation between pSTAT5 and GM-CSF levels emphasized that lower GM-CSF levels were required to induce STAT5 phosphorylation in presence of and without GM-CSF-neutralizing antibody when GM-CSF mRNA was used instead of recombinant GM-CSF. 2.3 Effects of recombinant GM-CSF vs. GM-CSF modified mRNA in presence of polyclonal GM-CSF-neutralizing antibody but after exchange of medium. It had successfully been shown that lower GM-CSF levels were required to induce STAT5 phosphorylation in presence of and without GM-CSF-neutralizing antibody when GM-CSF mRNA was used instead of recombinant GM-CSF. Therefore, it was now of interest to investigate whether GM-CSF mRNA would still prove superior when supernatant of cells was exchanged 4 h after treatment. Hereby, new GM-CSF-neutralizing antibody was supplied, but no more recombinant GM-CSF or mRNA. The time point for this medium exchange was chosen based on the approximate turnover time of recombinant GM-CSF in the lungs of healthy individuals (Eichinger, K. M., & Empey, K. M. (2017). Data describing IFNγ-mediated viral clearance in an adult mouse model of respiratory syncytial virus (RSV). Data in brief, 14, 272-277.). It was hypothesized, that also mRNA would theoretically be subject to fast turnover in an in vivo environment, if not taken up by cells within this time period. For this experiment, RAW264.7 cells were seeded in a 48-well format at a density of 60,000 cells/well.24 h after seeding, cells were either transfected with 0.3-30 ng/cm² GM-CSF mRNA or treated with 10, 100, or 1000 pg/mL recombinant GM-CSF. Simultaneously, cells were also supplemented with 5 µg/mL GM-CSF-neutralizing pAb.4 h after treatment, medium was aspirated and replaced with fresh medium without recombinant GM-CSF or mRNA, but again supplemented with 5 µg/mL polyclonal GM-CSF-neutralizing antibody. Supernatants and cells were harvested 4 h, 6 h, and 24 h after treatments. This experiment was conducted twice (n=2). Again, GM-CSF ELISA was conducted to quantify GM-CSF levels in supernatants of transfected cells (Figure 24). pSTAT5 western blots using cell lysates were conducted and pSTAT5 was semi- quantified via densitometry (Figure 23). It could be shown that STAT5 phosphorylation was only induced in immediate presence of recombinant GM-CSF and without GM-CSF-neutralizing antibody until medium exchange 4 h after treatment. Thus, 6 h after treatment (2 h after medium- exchange), no phosphorylated STAT5 above background levels could be detected anymore. In contrast, cells that had been transfected with GM-CSF mRNA still showed high levels of pSTAT5 6 h and even 24 h after treatment, thus 2 h and 20 h after medium exchange, respectively. This indicated that complexed mRNA had been taken up fast enough in order to exert its full effect even when medium was removed already 4 h after transfection. This conclusion could also be drawn when relative pSTAT5 abundance, semi-quantified via densitometry, was depicted in relation to GM-CSF levels in RAW264.7 supernatants at respective time points (Figure 24). The relation between pSTAT5 and GM-CSF levels emphasized that the STAT5-activating effect of recombinant GM-CSF, without presence of GM-CSF-neutralizing antibody, was immediately impaired as soon as recombinant GM-CSF was removed. In contrast, and advantageously GM-CSF mRNA was taken up by cells in sufficient amounts after 4 h in order to exert the STAT5-activating effect independently of any further extracellular turnover and independent of presence of GM-CSF-neutralizing antibody even until as long as 24 h after treatment. 4 Discussion and Conclusion It was shown that GM-CSF expressed by RAW264.7 cells transfected with GM-CSF-coding mRNA induced STAT5 phosphorylation via autocrine stimulation more effectively than recombinant GM-CSF added to supernatant. Cells transfected with mRNA secret GM-CSF which results in a higher local concentration of GM-CSF at the cell surface. The same GM-CSF concentrations obtained after transfection of mRNA, as were added using recombinant protein, induced stronger STAT5 phosphorylation. In contrast to recombinant GM-CSF added to the supernatant, activity of GM-CSF expressed by the macrophages from mRNA was surprisingly not strongly affected by polyclonal GM-CSF-neutralizing antibodies. While the STAT5-activating effect of recombinant GM-CSF was impaired as soon as it was removed from cells 4 h after treatment, the effect of GM-CSF mRNA remained unaltered. This highlights the overall advantage of GM-CSF mRNA in contrast to recombinant GM-CSF. mRNA is able to induce an auto-stimulatory GM-CSF signaling loop, and, once taken up by cells, is not subject to such fast turnover as is recombinant protein. Thus, GM-CSF mRNA can exert its STAT5-activating effect in a long-lasting and effective manner. Example 5 Single application study via sniffing in aged GM-CSF -/- mice to determine GM-CSF pharmacokinetic. This experiment was aimed at the assessment of GM-CSF pharmacokinetic upon one single application of ETH45 mRNA (ETH048T65, plasmid-based murine GM-CSF mRNA, SEQ ID NO:12, 100% N1-methyl-Pseudo-UTP formulated in Formulation I) or mRNA encoding eGFP (SEQ ID NO:32) via sniffing in aged GM-CSF -/- mice (strain number B6.129S-Csf2tm1Mlg/J, Jax Nr. 026812 - breeding colony from Biomere®) performed at the CRO Alpha Preclinical. After transfer of frozen BALF, plasma and lung samples, readouts were performed at Ethris GmbH. EGFP ELISA and mGM-CSF ELISA of lung samples, BALF, and plasma were performed. Dose-dependent levels of GM-CSF were quantified in lungs and BALF of aged GM-CSF-/- mice. GM-CSF levels were highest 5 h after treatment and indistinguishable from vehicle control 48 h after treatment. Sporadic GM-CSF levels above lower limit of quantification in plasma samples were likely caused by small injuries to lungs and subsequent spillover of GM-CSF into blood stream. Quantification of eGFP verified delivery of mRNA to lung. Overall, GM-CSF levels in lung and especially BALF were interpreted as sufficient and likely therapeutic, based on other data published in the literature (Zsengellér Z. K., et al., (1998). Adenovirus-mediated granulocyte- macrophage colony-stimulating factor improves lung pathology of pulmonary alveolar proteinosis in granulocyte-macrophage colony-stimulating factor-deficient mice. Human gene therapy, 9(14), 2101-2109.). Abbreviations & Definitions

1. Materials and Methods 1.1 Materials

Trans-Blot® Turbo™ Transfer System Bio-Rad 1704150 1.2 Methods 1.2.1 Animal treatment Aged GM-CSF-/- mice received a single dose of ETH45 (ETH048T65 mRNA, SEQ ID NO:12, modified with 100% N1-Methylpseudouridine, formulated as LiNP with Formulation I) via nasal sniffing. Nasal sniffing is a procedure in which a 50 µL aliquot is directly applied on the mice nostrils. The mRNA preparation is inhaled by the animal. Part of it remains in the nose and part of it deposits in the lungs. Four doses were tested (0.3, 1, 3, 10 µg. One additional group was treated with mRNA encoding eGFP (ETH003T49 mRNA modified with 25 % 2-Thiouridine/ 25 % 5-Methylcytidine, SEQ ID NO:33, formulated as LiNP with Formulation I) as reporter (10 µg) formulated as LiNP with Formulation I (ETH003T49). This was intended as a positive control for delivery of mRNA to the lung. Animals were sacrificed 5 h, 24 h, 48 h, 72 h, or 96 h after treatment. Three animals were treated per timepoint and dose. Body weight and body condition were evaluated directly before application and on a daily basis until the date of scheduled necropsy of each animal. Study Design

1.2.2 Sampling Animals were euthanized by CO2 asphyxiation to effect followed by thoracotomy and exsanguination. Whole blood samples were collected via cardiac puncture and processed to plasma and stored at nominally -70°C. Following euthanasia, BALF was collected by injecting and retrieving 0.8 mL PBS three times via 18-23G needle through the trachea. Animals may be inverted to allow spread into the lungs. The BALF was collected through the trachea via a syringe and stored at nominally -70°C. Following BALF collection, lungs were stored at nominally -70°C. 1.2.3 Lung homogenization Lysates of whole lungs were prepared. Organs were lysed in Triton X-100 lysis buffer. Prior to lysis, organs were weighed and aliquoted to Lysing Matrix D tubes at 300 mg per tube.500 µL lysis buffer was added. Tubes were stored on ice. Homogenization was conducted using the Fast- Prep24 Tissue Homogenizer (MP Biomedicals). Three homogenization cycles of 6.5 m/s and 20 sec were done. Subsequently. Homogenates were incubated on ice for 10 min for full lysis and then centrifuged 10 min at 4 °C at 14,000 rpm. Supernatant was collected and transferred to fresh reaction tube. Lysates were stored at -80 °C until analysis. 1.2.4 eGFP ELISA Lung lysate, BALF, and plasma were analyzed with eGFP ELISA. ELISA was conducted using the GFP SimpleStep ELISA (Abcam, ab171581) in a 384-well format, using respective pre-coated microplates (Abcam, ab203359). ELISA procedure was done according to manufacturer’s instructions, except that Triton X-100 lysis buffer was used as diluent of samples and for dilution of standard curve. Also, recombinant eGPF (Chromotek, egfp-250) was used, instead of kit standard. 1.2.5 GM-CSF ELISA hGM-CSF ELISA A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, 464718) was coated overnight at 4 °C with 6 µg/mL rat anti-human GM-CSF antibody (Abcam, ab106746) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, 37528) was added for blocking, using 50 µL per well and plate incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, a standard curve ranging from 1.2-20,000 pg/mL was prepared from recombinant human GM-CSF (BioLegend, 572904). Standard curve and samples were added to the plate using 20 µL per well and incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 1 µg/mL HRP-coupled rat anti-human GM-CSF (Abcam, ab106790) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Once more, the plate was washed 3x with PBST. Lastly, 20 µL TMB (Merck, CL07-1000mL) were added to all wells and the plate was incubated 5 min on bench top while protected from light. The reaction was stopped using 10 µL 1M H2SO4 and absorption was measured at 450/650 nm with microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with a 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using 0.05 % PBST. mGM-CSF ELISA A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, 464718) was coated overnight at 4 °C with 2 µg/mL rat anti-mouse GM-CSF antibody (Abcam, ab210896) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, 37528) was added for blocking, using 50 µL per well and the plate was incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, a standard curve ranging from 0.6-10,000 pg/mL was prepared from recombinant murine GM-CSF (BioLegend, 576306). Samples for generating a standard curve and measurement samples were added to the plate using 20 µL per well and incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 0.5 pg/mL HRP-coupled rabbit anti-mouse GM-CSF (Abcam, ab210896) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Then, the plate was washed 3x with PBST. Streptavidin-HRP solution (Abcam, ab210901) was diluted 1:500 and added to the plate using 20 µL per well. The plate was incubated 30 min at RT and 600 rpm. The plate was once more washed 3x with PBST. Lastly, 20 µL TMB (Merck, CL07-1000mL) were added to all wells and the plate was incubated 5 min on bench top while protected from light. The reaction was stopped using 10 µL 1M H₂SO₄ and absorption was measured at 450/650 nm with a microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with a 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using 0.05 % PBST. 2. Results 2.1 Body weight and clinical scoring of animals Body weight changes and clinical scoring showed that no ETH45 (GM-CSF mRNA)-induced effect on body weight or body condition was detected (see Figure 28). 2.2 GM-CSF ELISA GM-CSF expression is shown to be dose dependent in the lungs and the BALF (Figure 25). In the lungs GM-CSF expression was detected 5 hours post treatment at dose levels of 3 and 10 µg.24 hours post treatment GM-CSF levels decreased below the LLOQ except in 1 animal of the 10 µg dose group. In the BALF, levels above LLOQ were already observed at a dose level of 1 µg 5 hours post treatment with a peak at 10 µg. As in the lungs, a strong decrease of GM-CSF levels was observed 24 hours after treatment.48 hours after treatment GM-CSF levels decreased below the LLOQ at all dose levels which were applied in context of this study. 2.3 eGFP ELISA eGFP was detected in lung and at a lower amount in BALF (Figure 26). All GM-CSF levels quantified in the lungs were above the lowest limit of quantification, whereas only one out of three levels in BALF was above the lowest limit of quantification. This is consistent with expectations as eGFP is not a secreted protein. The detection in BALF may be caused by detached GFP- expressing cells. No eGFP was detected in plasma. Mean eGFP amount detected in lung was 1636pg/g. 2.4 Lung weights No impact of intranasal application of GM-CSF mRNA on lung weight was observed at any dose (Figure 27). 3. Discussion and Conclusion This experiment aimed at quantification of GM-CSF in lungs and BALF of aged GM-CSF-/- mice following single dose administration of GM-CSF mRNA at multiple dose level through nasal sniffing. GM-CSF levels in lungs and BALF were highest 5 h after treatment (max.1454 pg/g and 758 pg/mL, respectively) and indistinguishable from vehicle controls at 48 h after treatment (max. 34.92 pg/g (<LLOQ) and 9.46 pg/mL (<LLOQ), respectively). Sporadic GM-CSF levels above lower limit of quantification in plasma samples were caused by small injuries to lungs and subsequent spillover of GM-CSF into blood stream. There was no impact of GM-CSF mRNA administration on body weight or general body condition, suggesting GM-CSF mRNA was well tolerated by GM-CSF null mice in this study. Overall, GM-CSF levels in lungs and BALF were considered to be in a therapeutic range based on data published in literature (Zsengellér Z. K., et al., (1998). Adenovirus-mediated granulocyte- macrophage colony-stimulating factor improves lung pathology of pulmonary alveolar proteinosis in granulocyte-macrophage colony-stimulating factor-deficient mice. Human gene therapy, 9(14), 2101-2109.). Example 6 Pharmacological activity of mouse GM-CSF encoding mRNA in GM-CSF deficient mice This experiment was directed at investigating the pharmacological effect of intranasally administered GM-CSF mRNA (mouse GM-CSF-encoding mRNA ETH048T65 , SEQ ID NO:12, modified with 100 %-N1-Methylpseudouridine, formulated as LiNP with Formulation I) on pulmonary diseases progression at a treatment for a period of 5 weeks (and 3 times per week) in GM-CSF-deficient mice, a relevant pulmonary alveolar proteinosis (PAP) disease model. Intranasal treatment of GM-CSF-deficient mice using GM-CSF mRNA for a period of 5 weeks (3 treatments per week) was well tolerated and did not lead to any treatment related clinical findings at all dose levels (i.e.0.1 µg, 1 µg, 3 µg and 10 µg) included in this study. Treatment using GM-CSF mRNA resulted in dose-dependent increase of GM-CSF levels in Broncho Alveolar Lavage Fluid (BALF) in presence of a PAP phenotype. Moreover, treatment using GM-CSF mRNA resulted in significant improvement of disease relevant parameters in the BALF such as reduction of turbidity, surfactant protein levels, cellularity and count of macrophages. In addition, treatment using GM-CSF mRNA resulted in a significant morphological change of macrophages from large, lipid-filled to regular-sized with less or no lipid content containing macrophages. Abbreviations & Definitions

1.1 Materials and Methods 1.1.1. Materials

1.1.2 Methods 1.1.2.1. Animal housing All procedures were approved by the local animal welfare authorities (Government of Upper Bavaria) under the file number Az.2532.Vet_03-17-114 and conducted according to the German animal protection law (Animal Protection Act). Mice were housed under specific pathogen free conditions (facility tested negative for any FELASA listed pathogens according to the annual health and hygiene survey 2017) in individually ventilated cages under a circadian light cycle (lights on from 7 a.m. to 7 p.m.). Food and drinking water were provided ad libitum. After arrival, animals were given 7 days for acclimatization until they entered the study. 1.1.2.2. Intranasal administration of GM-CSF mRNA Animals were sedated by inhalation of a mixture of approximately 3% Isoflurane and pure oxygen using a whole-body inhalation chamber. As soon as animals reached the anesthetic stadium III- 2 of surgical tolerance (strongly reduced pedal withdrawal reflex), GM-CSF mRNA (SEQ ID NO:12) was applied as one bolus (50 µL) on the nose tip of the animals while the animal was held in perpendicular position. Animals were kept in perpendicular position until they showed signs of recovery from anesthesia. 1.1.2.3. Clinical observations Animals were examined clinically before and 5 hours after treatment and if required daily until the day of necropsy. Clinical examination consisted of 4 different categories which were scored separately. The scorings of each of the 4 categories were summarized to a total clinical score. A summarized score of more than 4 points or a score of more than 1 point in a single category were considered as moderate suffering and thereby as a humane endpoint. 1.1.2.4. Necropsy Animals were set under full anesthesia by intraperitoneal injection of Fentanyl/Midazolam/Medetomidin (0.05/5.0/0.5 mg/kg body weight). Capillary blood was taken from retrobulbar venous plexus using non-heparinized 0.8 mm capillaries and collected in EDTA tubes. Blood samples were centrifuged at 2.000 x g for 5 min at 4°C. Subsequently, mice were euthanized by cervical dislocation. 1.1.2.5. Preparation of tissues for bioanalytical assays The abdominal cavity was opened in the median axis. A careful cut was made in the diaphragm, which lead to atmospheric pressure in the thoracal cavity and immediate collapse of the lungs. All rips were dissected, and the trachea was exposed. A small incision was made in the trachea and a blunt ended 20 G steel needle inserted and fixed with a suture.0.8 mL PBS were injected and retrieved from the lungs for 3 times. Retained BAL fluid was stored on ice until further processing. After BALF retrieval the left kidney artery and vein were dissected. The small circulatory system was flushed with 3 mL PBS through the right ventricle using a 10 mL syringe and a 20 G needle. Subsequently, the heart was dissected from the heart-lung-block. The lungs were explanted and stored at -80°C until further processing. 1.1.2.6. Preparation of tissues for histological analysis Biobanking of tissue for histological analysis was planned for animals that had to be euthanized before official termination because they reach the humane endpoint and for 2 animals of each study group which were euthanized at the planned termination time point. The trachea was prepared and cannulated as outlined in section 1.1.2.5 and instilled with 0.8 ml of PFA. Lungs and trachea were explanted en bloc, fixed in 4 % neutral buffered PFA for 24 h and further processed for paraffin embedding. FFPE blocks were stored at RT until further processing (e.g., IHC). No animals had to be euthanized before official termination. 1.1.3. Quantitative and qualitative BALF cell count After the 1^st OD measurement, BALF samples were centrifuged at 400 x g for 5 min at 4°C. Then the 2^nd OD measurement was conducted. The BALF supernatant after the 2^nd measurement was transferred into a new microcentrifuge tube and stored at -80°C. BALF cells were resuspended in 500 µL PBS + 0.5 % BSA + 2 mM EDTA (= BALF Buffer). 50 µL of cell suspension (out of the 500 µL vial) were mixed with 50 µL trypan blue. After short mixing, 10 µL of the blue cell suspension was transferred to the Neubauer counting chamber. Cells were allowed to settle for 3-5 sec. For manual cell count a 20x magnification was used. Cells within all 4 grids were counted whereby a minimum cell number of 100 cells in all 4 grids was required. After counting of all 4 grids, the mean was calculated and multiplied by 2 (1:2 dilution of trypan blue). To achieve the cell number per mL, the result was multiplied by 10.000. Both counting areas per chamber were analyzed. 1.1.4. BALF droplet preparation BALF droplet preparation was performed by using 10 µL cell suspension in BALF Buffer. One droplet was placed in the center of the glass slide. After a short and carful shake, the glass slide was left unfixed and dried overnight. Droplet slides were used for HE and Wright Giemsa staining (to characterize cell types) and for Oil Red O staining (to identify foamy macrophages = PAP phenotype). For each staining, 5x droplet slides per animal were prepared and analyzed manually. 1.1.5. Measurement of BAL turbidity BAL turbidity was assessed as absorption of BALF at 600 nm. Absorption was analyzed using an automated plate reader. Samples were measured in technical duplicates using 100 µL/well in a 96-well format plate. After analysis of turbidity prior to centrifugation of samples, samples were re-collected from the plate and combined with sample again. 1.1.6. Total protein content of BAL supernatant Total protein content of BAL supernatant after centrifugation of BALF (5 min 400 ×g at 4 °C) was assessed using a bicinchoninic acid (BCA) assay (Pierce™ BCA Protein Assay, Thermo Fischer Scientific, Cat no.23225). The assay was conducted according to the manufacturer’s instructions. 1.1.7.1. STAT5 immunoprecipitation First, total protein content of lung lysate was measured using BCA assay according to the manufacturer’s instructions. Based on results of the BCA assay, a specific amount of total protein for immunoprecipitation (IP) was defined for all samples. All samples were supplemented with protease (PI)- and phosphatase-inhibitor (PHi). During all steps of the IP, samples and buffers were stored on ice. STAT5 immunoprecipitation was conducted as follows: ^ Transfer 50 µL beads to a tube, place on magnet, remove supernatant (SN), remove tube from magnet ^ Add antibody (5 µg) to beads in 200 µL PBS + 0.01 % Tween-20 (PBST) ^ Incubate bead-Ab solution 20 min at RT and 300 rpm ^ Place tube on magnet, remove supernatant, remove tube from magnet ^ Resuspend complex in 200 µL PSBT, wash by pipetting ^ Place tube on magnet, remove supernatant. ^ Add lung lysate to tube and resuspend ^ Incubate complex + lysate overnight (overnight) at 4 °C on a rolling device ^ Place tube on magnet, remove supernatant ^ Wash 3x using 200 µL PBS + PI + PHi ^ Resuspend bead-Ab-Ag complex in 100 µL PBS + PI + PHi, transfer to clean tube ^ Place tube on magnet, remove supernatant ^ Resuspend complex in 20 µL 50 mM Glycine (pH 2.8) + 10 µL premixed loading buffer + Reducing as required for western Blot, heat 10 min at 70 °C ^ Place tube on magnet and collect supernatant for western Blot ^ Store samples at -20 °C 1.1.7.2. STAT5 and pSTAT5 western blot 1.1.7.2.1. SDS-PAGE and Blotting Method For SDS-PAGE, Bolt™ 4-12% Bis-Tris Plus gels were used. SDS-PAGE was performed by applying 200 V for 30 min and using MOPS running buffer to obtain optimal resolution in the upper range. Transfer was performed using the TransBlot® Turbo^TM Transfer System (Bio-Rad) for 30 min. 1.1.7.2.2. Blocking and Antibody Incubation After transfer, membranes were blocked at RT for 1 h using 1x NET-Gelatin (NaCl-EDTA-Tris). Membranes were incubated agitating overnight at 4°C with the primary, unconjugated antibodies: anti-STAT5 (1:1000), anti-pSTAT5 (1:1000), or anti-GAPDH (1:10,000). After three washes (10 min each) with blocking solution at RT, horseradish peroxidase-conjugated secondary antibody (1:20,000) was added at RT for 1 h. Again, membranes were washed 3x 10 min with blocking solution at RT before signal development. 1.1.7.2.3. Chemiluminescent Signal Development Signals were visualized with a chemiluminescent substrate kit. For STAT5 membranes, Luminata Crescendo™ western HRP substrate is used. For pSTAT5 membranes, Luminata Forte was used. For GAPDH membranes, Luminata Classico was used. Membranes were incubated 1 min in ~5 mL substrate and subsequently visualized using the ChemiDoc™ MP System (Bio-Rad). 1.1.8. SP-D ELISA BALF supernatant and lung lysate were analyzed with SP-D ELISA in a 384-well format using the Mouse SP-D ELISA Kit (Abcam, ab240683) and pre-coated microplates (Abcam, ab203359). ELISA was conducted as recommended by manufacturer. Lung lysates were diluted 1:1000- 1:10,000, BALF was diluted 1:2000-1:200,000. as done in 1.2.5 above. SP-D concentrations quantified in lung lysate were back-calculated to concentration per lung weight. 1.1.9. GM-CSF ELISA BALF supernatant and lung lysate were analyzed with GM-CSF ELISA according to the following protocol: A 384-well Nunc™ Maxisorp™ plate (Thermo Fisher Scientific, 464718) was coated overnight at 4 °C with 2 µg/mL rat anti-mouse GM-CSF antibody (Abcam, ab210896) using 20 µL per well. After coating, the plate was washed 3x with PBST. Casein (Thermo Fisher Scientific, 37528) was added for blocking, using 50 µL per well and the plate was incubated 1 h at RT and 600 rpm on an orbital shaker. The plate was again washed 3x with PBST. Subsequently, a standard curve ranging from 0.6-10,000 pg/mL was prepared from recombinant murine GM-CSF (BioLegend, 576306). Samples for generating a standard curve and test samples were added to the plate using 20 µL per well and incubated 1.5 h at RT and 600 rpm. Next, the plate was washed 3x with PBST. Subsequently, 0.5 pg/mL HRP-coupled rabbit anti-mouse GM-CSF (Abcam, ab210896) detection antibody was added using 20 µL per well. The plate was incubated 1 h at RT and 600 rpm. Then, the plate was washed 3x with PBST. Streptavidin-HRP solution (Abcam, ab210901) was diluted 1:500 and added to the plate using 20 µL per well. The plate was incubated 30 min at RT and 600 rpm. The plate was once more washed 3x with PBST. Lastly, 20 µL TMB (Merck, CL07-1000mL) were added to all wells and the plate was incubated 5 min on bench top while protected from light. The reaction was stopped using 10 µL 1M H2SO4 and absorption was measured at 450/650 nm with a microplate reader. Concentrations were calculated using GraphPad Prism upon interpolation with 4PL standard curve. All dilutions, except that of coating antibody, which was diluted in PBS, were prepared using PBST. GM-CSF concentrations quantified in lung lysate were correlated to concentration per lung weight. 1.1.10. GM-CSF ADA ELISA Recombinant murine GM-CSF (BioLegend, 576306) was coated onto a 384-well plate overnight at 4 °C using 2 μg/mL and 20 μL per well. The plate was washed 3x with PBST, using an automated plate washer (Tecan, Infinite Mplex 200 Pro) and subsequently blocked with 50 μL casein per well for 1 h at RT and 600 rpm. The plate was again washed 3x with PBST. Plasma was diluted 1:2-1:16,384. Dilution series of plasma was added to plate, using 20 μL per well. As a positive control, biotinylated rabbit-anti-mouse GM-CSF antibody from Mouse GM-CSF Matched Antibody Pair Kit (Abcam, ab210896) was diluted 1:500, 1:2000, 1:10,000, and 1:100,000 (simulating decreasing concentration of anti-drug antibody) and added to plasma-free wells, using 20 µL per well. As a negative control, a goat anti-mouse IgG, IgM, IgA (H+L) HRP- coupled secondary antibody (Thermo Fisher Scientific, A-10668) was diluted 1:500 and added to further plasma-free wells, using 20 µL per well. The plate was incubated 1.5 h at RT and 600 rpm. The plate was washed 3x with PBST. Goat anti-mouse IgG, IgM, IgA (H+L) HRP-coupled secondary antibody was diluted 1:500 and added to all wells with plasma dilution series, using 20 μL per well. Streptavidin-HRP solution was diluted 1:500 and added to those wells previously incubated with biotinylated rabbit-anti-mouse GM-CSF antibody, using 20 µL per well. PBST was added to those wells previously already incubated with secondary antibody. The plate was incubated 1 h at RT and 600 rpm. The plate was washed 3x with PBST. 20 μL TMB solution (Merck, CL07-1000ML) was added to all wells. The plate was incubated 2 min at RT and 600 rpm while protected from light. The reaction was stopped using 10 μL 1 M H₂SO₂ per well. Absorption was measured at 450/650 nm using a plate reader. Subsequently, the OD was analyzed. In case an OD of a certain sample did not decrease distinctly with increasing dilution, this was rated as an indication for anti-drug antibodies within the respective sample. Dilution for coating was prepared using 1X PBS. All further dilutions and wash steps were conducted using 0.05 % PBST. 1.1.11. Urea normalization For urea normalization, plasma and BALF supernatant were analyzed using the Urea Nitrogen Colorimetric Detection Kit (Invitrogen, EIABUN). The assay was conducted according to the kit manual. For each animal, a factor for normalization was calculated by dividing the value obtained for plasma by the value obtained for BALF. Results from readouts (GM-CSF, SP-D, Turbidity) conducted to analyze BALF samples were later normalized by multiplication with the respective factor. 1.1.12. Oil Red O staining To quantify the PAP phenotype (e.g., lipid accumulation within macrophages = foamy macrophages), Oil Red O staining on BALF drops was performed according to manufacturer instructions. Two kits, one from Abcam (animals #1.1-1.8 (= 1 µg), #2.1-2.5 (= 0.3 µg) and #4.1- 4.5 (= vehicle)) and one from Polyscience (animals #3.1-3.8 (= 3 µg) and #4.6-4.8 (= vehicle)) were used. Details of each staining run were done according to the manufacturer’s instructions: Abcam kit: Slides were fixed in pre-cooled 4 % PFA solution for 10 min. After drying, slides were incubated for 5 min in absolute propylene glycol and transferred to heated (60°C) Oil Red O solution for 1 h. Differentiation was performed in 85% propylene glycol for 1 min, followed by rinsing in distilled water. Counterstaining with hematoxylin (1x short dip) was followed by mounting in aqua-poly mount. Polyscience Kit: Slides were fixed in pre-cooled 4 % PFA solution for 10 min. After drying (1 h), slides were incubated for 3 min in absolute propylene glycol and transferred to Oil Red O solution for 10 min at RT. Differentiation was performed in 85% propylene glycol for 2 min, followed by rinsing in distilled water.30 s counterstaining with hematoxylin was followed by rinse in tap water and mounting in aqua-poly mount. Quantification of Oil Red O positive macrophages was performed manually according to a previously defined grading scheme. Here, three categories, based on staining intensity, granularity and size were defined and called “strong,” “medium” and “faint” positive. In total 5 BALF drops per animal and 50 cells per slide were graded. 1.1.13. Hematoxylin/Eosin and Wright Giemsa staining for cell type characterization. In addition to the Oil Red O staining, BALF drops were stained with HE and WG to identify cell types. HE staining was performed as follows: After drying of the BALF drops, slides were fixed for 10 s with 4 % PFA solution. A wash step in distilled water followed and slides were placed in hematoxylin for 4 min. After rinsing in tap water, differentiation in HCL-Ethanol working solution by dipping 2 times followed. Again, a wash step in distilled water was performed and eosin staining for 3 min with subsequent dehydration via ascending ethanol series ending in xylol followed. Embedding was done with Roti-Histo Kit II. WG staining was performed as follows: After drying of the BALF drops, slides were fixed for 5 min in Methanol. Afterwards, slides were placed in WG solution for 5 min by slow agitation. A two times washing step in distilled water followed by PBS washing until no stain runs off the slides was performed. Incubation in fresh PBS for 1 min with subsequent wash in distilled water and drying for 2 h at RT followed. Slides were dipped several times in Xylol and mounted with Roti- Histo Kit II. Staining details of HE and WG stain were done following the manufacturer’s instructions. 1.1.14. SP-B, SP-C Immunohistochemistry on FFPE lungs FFPE blocks were generated and biobanked at RT. No SP-B or SP-C IHC was performed. 1.1.15. Statistical analysis Statistical differences between groups were calculated using Mann-Whitney’s U-Test. A p-value smaller than 0.05 was considered as statistically significant. 2. Study Design 2.2. Experimental Outline Animals were treated with item according to Table 17 and euthanized 24 hours after the last treatment. From study group 2 only 5 out of 10 animals were included in the study since it became evident during study conduct that the lowest dose was resulting only in a minimal pharmacodynamic response that could be sufficiently evaluated based on 5 animals. Table 17: Outline of study groups and applied dose levels.

Table 18: Sample list

3 Results 3.2. Calculation of individual BALF dilution factors Since bronchoalveolar lavage does not result in constant but in varying amounts of retrieved lavage fluid, a normalization using urea (i.e., blood and BALF urea nitrogen) was carried out to exactly calculate the concentration/value of each measured parameter in the alveolar surface lining fluid of the lungs. Blood and alveolar surface lining fluid do have equal concentrations of urea because the molecule can freely diffuse between the two compartments. Thus, urea concentration was measured in plasma and in the BALF. Subsequently, a dilution factor was calculated for each individual animal using the following formula: Dilution factor = Plasma Urea / BALF Urea Measured values of each assay performed in BALF was multiplied by the individual dilution factor. All BALF values measured from animal 4.1 (vehicle) were excluded from graphical and statistical analysis since the measured blood urea level was low (3.85 pg/mL) and not consistent with physiological urea levels. Animals 2.6, 2.7 and 28.8 did not enter the in vivo phase of the study. Table 19: Urea levels [pg/mL] in plasma and BALF and therefrom resulting dilution factors.

3.3 Optical density of airway surface lining fluid (ASLF) A dose-dependent decrease of optical density was observed in BALF upon treatment with 1 and 3 µg GM-CSF mRNA. Compared to vehicle a statistically significant (p = 0.0059) decrease of turbidity was observed (i.e. reduction of mean turbidity of 32.23 percent compared to vehicle) upon treatment with 3 µg of GM-CSF mRNA (Figure 29 and Table 20; Turbidity of ASLF following normalization to urea). However, no difference between vehicle and GM-CSF mRNA treated animals was observed when measuring optical density of BALF supernatant following centrifugation, suggesting a treatment-related reduction in ASLF turbidity.

Table 20: Descriptive statistics of optical density values

4.4 Total protein content in ASLF No difference between vehicle and ETH45 treated animals was observed with respect to the total content of protein in ASLF (Figure 30). 4.5 Content of SP-D protein in ASLF and lung tissue Decreasing levels of SP-D protein were observed for all ETH45 treated animals. Statistical significance (p = 0.008) and a reduction of SP-D by 41 percent was reached upon treatment with 3 µg ETH45 (Figure 31; Table 21).

Table 21: Descriptive statistics of SP-D levels in ASLF

No difference between vehicle and ETH45 treated animals was seen in lung tissue lysate which was derived from previously lavaged lungs (Figure 32). 4.6 BALF cell analysis A statistically significant (p = 0.02) decrease of total cells up to 42.9 percent was observed upon treatment with 3 µg ETH45 (Figure 33; Table 22). In contrast, no decrease of total cells compared to vehicle was observed upon treatment with 0.3 µg ETH45 while a trend towards lower cell numbers was observed following treatment with 1 µg ETH45. Table 22: Descriptive statistics of Cells in ASLF

Differential cell count of BALF cells showed a distinct distribution pattern in all groups, dominated by neutrophilic granulocytes (approximately 50 percent), lymphocytes (approximately 30 percent), macrophages (approximately 15 percent) and huge ghost like cells (approximately 5 percent) (Figure 34;Table 23). No statistically significant differences were observed for any of the groups, except for macrophages which were statistically significantly lower (43 percent less macrophages; p = 0.029) upon treatment with 3 µg ETH 45 compared to vehicle (Figure 34). Table 23: Descriptive statistics of Cell Characterization

4.7 Macrophage analysis by Oil Red O staining At the beginning of the Oil Red O macrophage analysis, only two categories “positive” and “negative” were counted. During the data analysis it became obvious that the intensity of staining, the granularity and the size of macrophages vary and that additional categories are necessary to quantify correctly. Therefore, three new categories, based on staining intensity, granularity and size were defined and were called “strong”, “medium” and “faint” positive. Due to the switch of the analysis method, not all groups were counted the same way. Animals #1.1, 2.1 and 4.1 were graded for “positive” and “negative” only. Animals #1.2-1.5, #2.2-2.5 and #4.2-4.5 were graded for “strong”, “faint” and “negative”. Animals #1.6-1.8, #3.1-3.8 and #4.6-4.8 were graded with the final grading scheme “strong”, “medium”, “faint” and “negative”. When analyzing the whole dataset a clear treatment effect of ETH45 was observed (Figure 35, Table 2). 3 µg ETH45 resulted in a 61% reduction of strong positive macrophages which was statistically significant (p = 0.0003). This large reduction of strong positive macrophages as a hallmark of disease was paralleled by a 30% increase of medium (p = 0.012) and 61% increase of faint (p = 0.0057) positive macrophages. Table 24: Descriptive statistics of Macrophage phenotype by Oil Red O staining – different grading schemes

Analysis of groups that underwent the same grading scheme (Figure 41: three animals of vehicle and 1 µg ETH45 group, and eight animals of 3 µg ETH45 group) revealed comparable ETH45 treatment related effects. Treatment with 3 µg ETH45 resulted in 50% reduction in strong positive macrophages (i.e. large, lipid-filled macrophages) (Figure 36, Table 25). In parallel, the proportion of medium and faint positive macrophages and also negative macrophages increased by ~2 fold (i.e. regular-sized macrophages with limited lipid or no lipid content). The differences in the percentage of reduction are related to the different grading schemes. At the beginning “faint” and “medium” positive cells were counted as strong positive. Therefore, an overestimation of “strong” positive macrophages by comparing all groups side by side exists. Nevertheless, the treatment effect of 3 µg ETH45 resulted in a significant (p= 0.012) reduction of strong positive macrophages compared to vehicle controls (n=8).

Table 25: Descriptive statistics of Macrophage phenotype by Oil Red O staining – same grading scheme

It was apparent that all types of macrophages were present in all animals independent of ETH45 (GM-CSF Murine GM-CSF mRNA, 100% N1-methyl pseudouridine SEQ ID NO:12) treatment. However, treatment with ETH45 resulted in prominent reduction of number of macrophages with strong lipid staining, with a high number of lipid-containing granules and with large diameter. Exemplary bright field images are shown in Figure 37). 4.8 Concentration of GM-CSF in ASLF and lung tissue Dose-dependent increase of GM-CSF was observed in the ASLF 24 hours after the last treatment (Figure 38, Table 26). While most animals in the vehicle group had undetectable GM-CSF levels, GM-CSF could be measured in all animals treated with 1 and 3 µg ETH45. Due to high variation between the single values, the difference between vehicle and treatment groups did not reach statistical significance.

Table 26: GM-CSF levels in ASLF [pg/mL] (lower limit of quantification is ~240)

*In total, in 6 out of 8 vehicle samples no GM-CSF was detectable. ** In total, in 2 out of 5 samples from no GM-CSF was detectable in 0.3 µg dose group. There was also a trend towards slightly higher GM-CSF concentrations in lung tissue (Figure 39, Table 27) However, lungs were previously lavage, thereby removing excreted GM-CSF. Furthermore, GM-CSF is a secreted protein and thus not primarily detectable at large quantities in lung tissue.

Table 27: GM-CSF levels in lung lysate [pg/g] (lower limit of quantification is ~200]

4.9 Tolerability of treatment ETH45 (murine GM-CSF mRNA, SEQ ID NO:12, 100% N1-Methylpseudouridine) was well tolerated, and no treatment related adverse effects based on clinical observations were observed following drug administration for 5 weeks and 3 times per week. Development of body weight is considered to be the most important parameter for interpreting the animals’ condition over longer treatment periods. As shown in Figure 40, all animals gained weight at the same level compared to vehicle controls (measured in percent weight change compared to day 1) during the entire period of the study. 5 Discussion and Conclusion ETH45 was well tolerated when administered via nasal instillation to GM-CSF-deficient mice for 5 weeks and 3 times per week. Results of the present study demonstrate that treatment with murine GM-CSF mRNA (ETH45, SEQ ID NO:12, 100% N1-Methylpseudouridine) resulted in dose-dependent increases of GM- CSF level in BALF in the presence of a PAP phenotype. Treatment with mRNA was associated with significant improvement of BALF-related endpoints that are relevant to PAP in this model and to human disease, including reduction of turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts. In addition, treatment with ETH45 resulted in a significant shift in the phenotype of macrophages from large, lipid-filled macrophages, which are considered a hallmark of PAP towards regular-sized macrophages with limited lipid or no lipid content. Example 7 Effect of human GM-CSF mRNA (SEQ ID NO:7, 100% N1-Methylpseudouridine) on phosphorylation of STAT5 in presence of GM-CSF-neutralizing antibody in human THP-1 cells Following in vitro and in vivo studies with mRNA coding for murine GM-CSF, the aim of this study was to investigate the effect of recombinant human GM-CSF (rec. hGM-CSF) versus modified mRNA coding for human GM-CSF (SEQ ID NO:7, 100% N1-Methylpseudouridine) on the activation of the GM-CSF pathway in human THP-1 macrophages in presence of an hGM-CSF- neutralizing antibody. Pathway activation was defined by phosphorylation of STAT5. 1.1 Materials and Methods 1.1.1. Materials

Table 30

1.1.2. Methods 1.1.2.1. Cultivation and differentiation of THP-1 cells THP-1 cells were cultivated in RPMI-1640 GlutaMAX™ supplemented with 10 % FBS and 0.05 mM 2-Mercaptoethanol. Undifferentiated cells were cultivated in suspension and required to not exceed a density of 1x10⁶ cells/mL. For subcultivation, 2-8x10⁵ cells/mL were seeded into a new flask. For differentiation of THP-1 cells into adherent monocytes, 3.5x10⁵ cells/mL were seeded in a 48- well plate together with 200 nM PMA, all within a volume of 200 µL. Cells were incubated with PMA for 72 h (Fri-Mo). Subsequently, medium was aspirated, cells were washed once with PSB and then incubated without PMA for further 24 h. During differentiation and subsequent resting phase, cells were not moved. Upon differentiation, cells became adherent and could be used for subsequent experiments (Tue). PMA solution was prepared as follows: ^ 20 mM stock solution: dissolve 10 mg PMA in 810 µL DMSO ^ 200 nM working solution: serially dilute PMA stock solution 1:1000 and subsequently 1:100 in cultivation medium in order to obtain 200 nM 1.1.2.2 Treatment, transfection, and harvest of differentiated THP-1 cells ^ STAT5 activation upon rec hGM-CSF vs GM-CSF mRNA formulated as LiNP with Formulation I +/- pAb (no medium-exchange) Three 48-well plates, seeded with 16 wells of differentiated THP-1 cells, were required to collect samples 4 h, 6 h, and 24 h after treatment/transfection. Treatment and transfection were conducted according to layout shown in Table 28. Cells were treated with 0, 10, 100, and 1,000 pg/mL recombinant hGM-CSF with or without 5 µg/mL hGM-CSF-neutralizing antibody. Remaining cells were transfected with doses of 2, 4, and 9 ng/cm² (hGM-CSF mRNA formulated as LiNP with Formulation I) or 9 ng/cm² Stop mRNA (formulated as LiNP with Formulation I), using a transfection volume of 25 µL. LiNP was diluted in vehicle (10 % sucrose), according to calculations shown in Table 29. Again, simultaneously, cells were incubated with or without 5 µg/mL hGM-CSF-neutralizing antibody in addition. Subsequently, after 4 h, 6 h, and 24 h, medium was collected and stored at -80 °C until analysis with hGM-CSF ELISA. Cells were washed with PBS-/- and stored at -80 °C until lysis for western blot. Table 28: 48-well plate layout for treatment and transfection

Table 29: LiNP-dilution for transfection

STAT5 activation upon rec hGM-CSF vs hGM-CSF mRNA (SEQ ID NO:7 (100% N1- Methylpseudouridine), formulated as LiNP with Formulation I +/- pAb (medium-exchange) Three 48-well plates, seeded with 16 wells of differentiated THP-1 cells, were required to collect samples 4 h, 6 h, and 24 h after treatment/transfection. Treatment and transfection were conducted according to layout shown in Table 28. Cells were treated with 0, 10, 100, and 1,000 pg/mL recombinant hGM-CSF with or without 5 µg/mL hGM-CSF-neutralizing antibody. Remaining cells were transfected with doses of 2, 4, and 9 ng/cm² hGM-CSF mRNA (100% N1- Methylpseudouridine, SEQ ID NO:7, formulated as LiNP with Formulation I) or 9 ng/cm² Stop mRNA (formulated as LiNP with Formulation I), using a transfection volume of 25 µL. LiNP was diluted in vehicle (10 % sucrose), according to calculations shown in Table 29. Again, simultaneously, cells were incubated with or without 5 µg/mL hGM-CSF-neutralizing antibody in addition.4 h after treatment and transfection, medium and cells from 4 h-plate were collected. On both other plates, medium was aspirated and replaced with fresh medium without treatment or LiNP but again +/- pAb. Subsequently, 6 h-, and 24 h-samples were collected without further adjustments. Medium was collected and stored at -80 °C until analysis with hGM-CSF ELISA. Cells were washed with PBS-/- and stored at -80 °C until lysis for western blot. Western blot Sample preparation Cells were lysed for western blot using 60 µL M-Per supplemented with 1X Phosphatase Inhibitor, 1X Protease Inhibitor, and 1X DNase I per well. Plates with cells in lysis buffer were incubated 30 min on ice until fully lysed. Lysates were stored at -80 °C until western blot. For western blot, whole lysis volume in plates (60 µL) was heated 10 min at 70 °C at 350 rpm with 37.5 µL Loading buffer and 15 µL Reducing Agent per well. SDS-PAGE and Blotting Method For SDS-PAGE, Bolt™ 4-12% Bis-Tris Plus gels (15 wells) were used. Per well, 15 µL sample (including Loading buffer + Reducing mix) were loaded. SDS-PAGE was performed by applying 200 V for 45 min and using MOPS running buffer to obtain optimal resolution in the upper range. Transfer was performed using the TransBlot® Turbo^TM Transfer System (Bio-Rad) for 30 min. Blocking and Antibody Incubation After transfer, membranes were blocked 1 h at RT using 1X NET-Gelatin (NaCl-EDTA-Tris).1 L of NET-Gelatin was prepared using 250 mL 2 M TRIS pH7.5, 100 mL 0.5 EDTA pH 8.0, 67.7 g NaCl, 25 g Gelatin, 5 mL Triton X-100, and ddH2O. Membranes were incubated agitating overnight at 4 °C with respective primary antibody* using the following dilutions: Rabbit anti-pSTAT5: 1:1,000 Rabbit anti-GAPDH: 1:10,000 Membranes were washed 3x10 min at RT with NET-Gelatin and subsequently incubated 1 h at RT with secondary antibody using the following dilution: Goat anti-rabbit: 1:20,000 Again, membranes were washed 3x10 min at RT with NET-Gelatin before signal development. ^ Chemiluminescent Signal Development Signals are visualized with a chemiluminescent substrate kit. For GAPDH membranes, Luminata Classico was used. For pSTAT5 membranes, Luminata Forte was used. Membranes were incubated 1 min (Classico) or 2 min (Forte) in 10 mL substrate while agitating at RT. Subsequently, signals were visualized using the ChemiDoc™ MP System (Bio-Rad). For Classico membrane, 10 pictures were taken over 50 sec exposure time, starting after 5 sec. For Forte membranes, 12 pictures were taken over 120 sec exposure time, starting after 10 sec. For evaluation, always the last image before over-exposure was chosen. ^ Semi-quantification of pSTAT5 pSTAT5 bands were semi-quantified by normalization to GAPDH bands using the BioRad® program ImageLab. ^ hGM-CSF ELISA Cell supernatants were analyzed with hGM-CSF ELISA following the method described above in 1.1.9 and 1.1.10. 2 Results 2.1. Study design Following in vitro and in vivo PoC studies with mRNA coding for murine GM-CSF, the aim of this study was to investigate the effect of recombinant hGM-CSF versus mRNA coding for human GM-CSF on the activation of the GM-CSF pathway in human THP-1 macrophages in presence of an hGM-CSF-neutralizing antibody. Pathway activation was defined by phosphorylation of STAT5. For this purpose, differentiated human THP-1 cells were treated with recombinant hGM-CSF or transfected with hGM-CSF mRNA, formulated as LiNP with Formulation I - all in the presence of an hGM-CSF-neutralizing polyclonal antibody. Hereby, PAP-relevant hGM-CSF doses of 10, 100, and 1,000 pg/mL were employed. These concentrations were either added using the recombinant protein or cells were transfected with the LiNP-doses that were previously shown to yield 10, 100, and 1,000 pg/mL hGM-CSF 4 h after transfection. The timepoint of 4 h was chosen based on the turnover of recombinant GM-CSF in the lung of mice (Eichinger et al., Cytokine, 2017). The dose range of 1-1,000 pg/mL (1 pg/mL was dropped, as this is a concentration below the lower limit of quantification of the hGM-CSF ELISA) was chosen specifically to represent the range of GM-CSF levels that are present in lungs of healthy individuals and in those of PAP patients (Carraway et al., Am J Respir Crit Care Med., 2000). An antibody concentration of 5 μg/mL was chosen based on antibody concentrations found in PAP patients (Sakagami et al., Am J Respir Crit Care Med., 2010). 2.2. Experimental Outline Exp-1: STAT5 activation upon rec hGM-CSF/ mRNA formulated as LiNP with Formulation I +/- pAb, no medium-exchange Exp-2: STAT5 activation upon rec hGM-CSF/ mRNA formulated as LiNP with Formulation I +/- pAb, medium-exchange after 4 h Both experiments were conducted three times as biological replicates with independent transfections. (n=3) 2.3. hGM-CSF mRNA induceds STAT5 activation is more effective than rec hGM-CSF-induced STAT5 activation and independent of hGM-CSF-neutralizing polyclonal antibody. Differentiated THP-1 cells were treated with 10/100/1000 pg/mL rec hGM-CSF or transfected with 2/4/9 ng/cm² hGM-CSF mRNA formulated as LiNP with Formulation I, both in combination with and without 5 µg/mL hGM-CSF-neutralizing pAb. No medium-exchange was conducted after initial treatment/transfection. Cells were collected 4 h, 6 h, or 24 h after treatment/transfection and lysed for pSTAT5 western blot. All western blots are shown in Figures 48-50. As shown in Figure 42, rec hGM-CSF was observed to induce dose-dependent STAT5 activation. Hereby pSTAT5 levels, however, were shown to decrease over time. In presence of hGM-CSF- neutralizing antibody, no STAT5 activation via rec hGM-CSF was observed. In contrast, hGM- CSF mRNA induced STAT5 activation to a similar extent upon all employed doses, but to a higher extent in the low doses compared to recombinant hGM-CSF and independently of presence of hGM-CSF-neutralizing antibody. In addition to investigation of activation of STAT5 induced by either recombinant hGM-CSF or hGM-CSF mRNA, also levels of hGM-CSF in supernatant collected 4 h, 6 h, or 24 h after treatment/transfection were quantified to verify intended vs. present concentrations. As can be seen in Figure 43, hGM-CSF levels upon transfection of hGM-CSF mRNA were below intended nominal yields (dotted line in graph) and even below levels of rec hGM-CSF in supernatant 4 h after initial treatment/transfection, which was the timepoint of interest (GM-CSF turn-over, see 2.1 in this Example), for which required transfection doses had been determined before. However, this showed that even though the lowest dose of hGM-CSF mRNA resulted in hGM-CSF yields below the lower limit of quantification (20 pg/mL), it was able to induce similar levels of pSTAT5 as highest dose of rec hGM-CSF (1,000 pg/mL). hGM-CSF levels in supernatant of cells treated or transfected in presence of hGM-CSF-neutralizing antibody could not be quantified accurately, as antibody was observed to interfere with ELISA. Relative pSTAT5 abundance was also correlated to hGM-CSF concentration in supernatant (Figure 44). This emphasized the effects described above: rec hGM-CSF was observed to induce dose-dependent STAT5 activation which declined over time, whereas STAT5 activation upon hGM-CSF mRNA was dose-independent and remained stable across all observed timepoints. In addition, whilst presence of hGM-CSF-neutralizing antibody completely abrogated STAT5 activation via rec hGM-CSF, STAT5 activation upon ETH45 remained unaffected. 2.4. ETH45-induced STAT5 activation is more effective than recombinant hGM-CSF-induced STAT5 activation, independently of hGM-CSF-neutralizing polyclonal antibody, and independently of medium-exchange. Differentiated THP-1 cells were treated with 10/100/1000 pg/mL rec hGM-CSF or transfected with 2/4/9 ng/cm² hGM-CSF mRNA formulated as LiNP with Formulation I, both in combination with or without 5 µg/mL hGM-CSF-neutralizing pAb. At 4 h after treatment/transfection, medium- exchange was conducted. Cells were hereby also supplied with or without hGM-CSF-neutralizing pAb anew. Cells were collected 4 h, 6 h, or 24 h after initial treatment/transfection and lysed for pSTAT5 western blot. All western blots are shown in Figures 51 to 53. As shown in Figure 45, recombinant hGM-CSF was observed to induce dose-dependent STAT5 activation. However, upon medium-exchange pSTAT5 levels rapidly decreased to below background. No STAT5 activation could be detected 24 h after initial treatment. In presence of hGM-CSF-neutralizing antibody, no STAT5 activation via recombinant hGM-CSF was observed at all. In contrast, and surprisingly, hGM-CSF mRNA was again observed to induce strong STAT5 activation to a similar extent upon all employed doses, independently of medium-exchange and independently of the presence of hGM-CSF-neutralizing antibody. In addition to activation of STAT5 induced by either recombinant hGM-CSF or hGM-CSF mRNA, also levels of hGM-CSF in supernatant collected 4 h, 6 h, or 24 h after treatment/transfection were quantified in order to verify intended concentrations. As can be seen in Figure 43, hGM-CSF levels upon transfection with ETH45 were very similar to concentrations of rec hGM-CSF and also very close to intended nominal yields in supernatant 4 h after initial treatment/transfection. Quantifiable hGM-CSF in supernatant of cells treated with rec hGM-CSF was diminished upon medium-exchange. Some residual hGM-CSF in supernatant of cells treated with highest dose of 1,000 pg/mL rec hGM-CSF could still be quantified. hGM-CSF concentrations quantified in supernatant of cells transfected with hGM-CSF mRNA increased towards 24 h after initial transfection. However, no distinct increase from 4 h to 6 h after initial transfection was quantified, implicating that possibly LiNP had not yet been taken up fully at 4 h after transfection and thus slightly reduced translation may occur after medium-exchange than observed in experiment without medium exchange after four hours Again, hGM-CSF levels in supernatant of cells treated or transfected in presence of hGM-CSF-neutralizing antibody could not be quantified accurately, as presence of the antibody was observed to interfere with ELISA. Relative pSTAT5 abundance was again also correlated to hGM-CSF concentration in supernatant (Figure 47). This emphasized the effects described above: rec hGM-CSF was shown to induce dose-dependent STAT5 activation which was abrogated abruptly upon medium-exchange and thus removal of rec hGM-CSF, whereas STAT5 activation upon hGM-CSF mRNA was dose- independent and remained unaffected by medium-exchange and stable across all observed timepoints. In addition, whilst presence of hGM-CSF-neutralizing antibody completely abrogated STAT5 activation via rec hGM-CSF, STAT5 activation upon ETH45 remained unaffected. 3 Discussion and Conclusion This study demonstrates a superior effect of a nucleic acid expressing GM-CSF, and in particular hGM-CSF mRNA, on STAT5 activation in human THP-1 macrophages in comparison to recombinant hGM-CSF. Low levels of hGM-CSF (<20 pg/mL) in supernatant of cells transfected with ETH45 were shown to induce similar or even higher pSTAT5 levels than high doses of recombinant hGM-CSF (1,000 pg/mL) already 4 h after transfection/treatment. Additionally, STAT5 activation upon hGM-CSF mRNA was shown to be unaffected by presence of hGM-CSF- neutralizing antibody and independent of medium-exchange at 4 h after transfection, and by this the removal of any residual LiNP and already translated hGM-CSF. In contrast, STAT5 activation upon recombinant hGM-CSF was completely abolished in presence of hGM-CSF-neutralizing antibody and abruptly abrogated upon medium-exchange at 4 h after treatment, and by this the removal of all available hGM-CSF in supernatant. Example 8 Confirmation of ex vivo activity of mGM-CSF expressed in GM-CSF-/- mice upon mRNA delivery The aim of this Example is to confirm the activity of mGM-CSF (murine GM-CSF) mRNA administered intranasally to GM CSF-/- mice via sniffing in Example 6. The mRNA activity was investigated ex vivo. For this purpose, murine RAW264.7 macrophages were incubated for 1 h with BALF from treated mice that was collected 24 h after last treatment with modified mRNA coding for GM-CSF. As a control, cells were incubated with recombinant mGM-CSF (BioLegend, 576306) using the same concentrations that were quantified in BALF. Subsequently, STAT5 and pSTAT5 western blots were conducted with cell lysates in order to show GM-CSF-induced STAT5 activation. Summary & Conclusion The activity of mGM-CSF expressed in GM-CSF-/- mice upon mRNA delivery (Example 6) was confirmed. Incubation of RAW264.7 cells with BALF from treated GM-CSF-/- mice was shown to induce STAT5 phosphorylation, whilst incubation of cells with BALF from vehicle-treated mice did not induce STAT5 phosphorylation. All employed dilutions of BALF (undiluted, 1:2, and 1:4) were observed to induce similar levels of pSTAT5. As a control, RAW264.7 cells were also treated with 10.000 pg/mL of recombinant mGM-CSF in PBS. General Information Table 30 – Test Item and Test System

Material and Methods Table 31 – Materials

Table 32 - Devices

Methods Cultivation of RAW264.7 cells Murine RAW264.7 macrophages were cultivated in DMEM GLutaMax™, supplemented with 10 % FBS. For subcultivation or seeding, cells were detached from flask using a scraper. Cells were centrifuged 5 min at ~300 x g. Medium was aspirated and cells are resuspended in fresh medium. Cells were counted using a Countess cell counter. For this experiment, cells were then seeded at a density of 60,000 cells in 200 µL per well in a 48-well plate. Treatment and harvest of RAW264.7 cells 24 h after seeding, medium was aspirated and cells incubated 1 h at 37 °C with either 100 µL BALF from Example 6 (animal 1.7 (dose: 1 µg) or animal 4.1 (mice treated with vehicle), or with 100 µL recombinant mGM-CSF, diluted in PBS. Both BALF and solution of recombinant GM-CSF were employed undiluted and in two further serial 1:2-dilutions (1:2 and 1:4). Previous experiments had shown that a recombinant mGM-CSF concentration as low as 10 pg/mL was sufficient to induce STAT5 phosphorylation in vitro. As a positive control, cells were incubated with 10,000 pg/mL recombinant GM-CSF. As a negative control, cells were incubated with PBS. 1 h after treatment, cells were washed with PBS and lysed in M-Per buffer, supplemented with 1x protease inhibitor and 1x DNAse I, using 60 µL per well for STAT5 and pSTAT5 western blot. Western blot layout is shown in Figure 54. Western blot Sample reducing Per well, 15 µL of Loading buffer and 6 µL of Reducing Agent were added and the plate was incubated 10 min at 70°C and 350 rpm. SDS-PAGE and Blotting Method For SDS-PAGE, Bolt™ 4-12% Bis-Tris Plus gels were used. Per pocket, 30 µL sample was loaded. SDS-PAGE was performed by applying 200 V for 30 min and using MOPS running buffer to obtain optimal resolution in the upper range. Transfer was performed using the TransBlot® Turbo^TM Transfer System (Bio-Rad) for 30 min. Blocking and Antibody Incubation After transfer, the membranes were blocked at room temeperature for 1 h using 1x NET-gelatine (NaCl-EDTA-Tris). Membranes were incubated agitating overnight at 4 °C with the primary, unconjugated antibodies: anti-pSTAT5 (1:1000), anti-STAT5 (1:1000), or anti-GAPDH (1:10,000). After three washes (10 min each) with blocking solution at room temperature, horseradish peroxidase-conjugated secondary antibody 1:20,000) was added at room temperature for 1 h. Again, membranes were washed 3 times for 10 min with blocking solution at room temperature before signal development. Chemiluminescent Signal Development Signals were visualized with a chemiluminescent substrate kit. For pSTAT5 membranes, Luminata Forte Western HRP substrate was used. For STAT5 membranes, Luminata Crescendo was used. For GAPDH membranes, Luminata Classico was used. Membranes were incubated 2 minutes in ~5 mL substrate and subsequently visualized using the ChemiDoc™ MP System (Bio- Rad). Results As can be seen in Fig 54, BALF from treated mouse 1.7 (1 µg dose group) induced STAT5 phosphorylation in RAW264.7 cells, while BALF from vehicle-treated mouse 4.1 does not induce STAT5 phosphorylation in RAW264.7 cells. Incubation with recombinant mGM-CSF was shown to induce STAT5 phosphorylation in a dose-dependent manner as well. In contrast, incubation with BALF did not have a dose-dependent effect. Incubation with only PBS did not induce STAT5 phosphorylation. 1:2- and even 1:4-dilution of BALF was not shown to reduce pSTAT5 levels compared to undiluted BALF. Thus, STAT5 levels remained stable in RAW264.7 cells, independent of treatment. Discussion and Conclusion The activity of mGM-CSF expressed in GM-CSF-/- mice upon mRNA delivery was confirmed. Incubation of RAW264.7 cells with BALF obtained from mRNA-treated GM-CSF-/- mice was shown to induce STAT5 phosphorylation, whilst incubation of cells with BALF from vehicle-treated mice did not induce STAT5 phosphorylation. All employed dilutions of BALF (undiluted, 1:2, and 1:4) were observed to induce similar levels of pSTAT5 which indicates that the maximum of STAT phosphorylation is achieved with all tested dilutions and is indicative of the potency of the mRNA formulation of the invention. Recombinant mGM-CSF in PBS was added to the cell cultures as control (10.000 pg/mL). This experiment thus shows that the mRNA administered to GM-CSF-/- mice actively induces GM-CSF expression in vivo and that the GM-CSF derived from said expression is present in mice BALF and induces efficient ex-vivo GM-CSF expression in RAW264.7 cells at higher levels, equivalent or higher to 10.000 pg/mL of recombinant GM-CSF. Example 9 Production and effects of modified mRNA comprising 5-Iodouridine and 5-Iodocytidine. The aim of this Example is to show the relevance of uridine and cytidine iodine-containing modifications in immunogenicity of exogenous mRNA in cells. Using vector carrying luciferase, mRNA was produced by vitro transcription. To ensure efficient ribosomal translation and prevention of exonuclease degradation, capping of mRNA was done with m7G by Vaccinia Virus Capping Enzyme and O-Methyltransferase. Transfection of modified mRNA. 20.000 A549 cells per well, were transfected using a lipoplex (Lipid (Lipofectamin2000): RNA = 2:1) in 150 µL MEM + 10 % FCS + 1 % P/S. Luciferase induction and immune response was monitored by FACS (Mean Fluorescence Intensity (MFI) 24 hours after transfection. Immune response was quantified using ELISA of IL-6. A significant reduction of cytokine release was measured for mRNAs formulated in an in-vitro reaction containing two modifications: between 20%-40% I5U and between 2%-10% I5C. Fig 55 shows cell immune response to modified mRNA measured by IL6 ELISA.

Claims

New PCT Application Ethris GmbH Vossius Ref.: AD3818 PCT S3 CLAIMS 1. A nucleic acid comprising a sequence encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof, preferably wherein the nucleic acid comprises a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73.

2. The nucleic acid according to claim 1, wherein the nucleic acid is selected from a polynucleotide DNA or a polynucleotide RNA, preferably wherein said polynucleotide RNA is an mRNA.

3. The nucleic acid according to anyone of claims 1 or 2, wherein the nucleic acid is a modified nucleic acid comprising a combination of unmodified nucleosides and chemically modified nucleosides. 4. The nucleic acid according to claim 3, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non- immunogenic. 5. The nucleic acid according to claim 3 or 4, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2- thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio- 1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy- pseudouridine, 4-thio-1-methyl-pseudouridine,

4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine,

5-iodo- citosine and combinations thereof.

6. The nucleic acid according to claim 1 to 5, wherein the nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5- methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine.

7. The nucleic acid according to anyone of claims 1 to 5, wherein the nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1- methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine.

8. The nucleic acid according to claim 1 to 5, wherein the nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5-Iodocytidine.

9. The nucleic acid according to anyone of claims 1 to 5, wherein the nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ).

10. The nucleic acid according to any one of claims 1 to 9, further comprising any of the following: (a1) a 5' UTR upstream of the coding sequence, preferably wherein the 5' UTR is a sequence selected from the list consisting of: the sequence GGGAGACGCCACC (SEQ ID NO:3 or 46), the sequence GGGAGACTGCCACC (SEQ ID NO:34 or 69), the sequence GGGAGACGCCAAG (SEQ ID NO:37 or 71), the sequence GGGAGACGCCAAG (SEQ ID NO:35 or 70), a CYBA 5´UTR (SEQ ID NO:15 or 51), 5´TISU UTR (GCCAAG), human alpha globin 5´UTR (SEQ ID NO:18 or 54), 5´UTR of SEQ ID NO:19 or 55, a SP30 Spacer 5´ UTR (SEQ ID NO:21 or 57) and/or the 5' UTR of SEQ ID NO:22 or 58, and (a2) when the nucleic acid is DNA, upstream of (a1) a promoter which is recognized by a DNA-dependent RNA polymerase, preferably a promoter with a sequence selected from TAATACGACTCACTATA (SEQ ID NO:4) which is recognized by a T7 DNA-dependent RNA polymerase, and (a3) a 3' UTR, preferably a 3' UTR selected from 3'-UTR selected from the list consisting of: 3'UTR of the sequence 5'-TTCG-3', the UTR sequence 5'- CACCGGGCAATACGAGCTCAAGCCAGTCTC (SEQ ID NO:14 or 50), CYBA 3´UTR (SEQ ID NO:16 or 52), and/or 3' UTR of SEQ ID NO:20 or 56, and/or (a4) a poly(A), preferably a segmented poly(A).

11. The nucleic acid according to anyone of claims 2 to 10, wherein the modified mRNA encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein is codon optimized, preferably wherein the modified mRNA is codon optimized for expression of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein in a human.

12. The nucleic acid according to any one of claims 1 to 11, wherein the nucleic acid is produced/transcribed using an in vitro system, such as in vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase.

13. The nucleic acid according to any one of claims 1 to 12, wherein the nucleic acid is comprised in a vector, preferably an expression vector, more preferably the vector of SEQ ID NO:8 or SEQ ID NO:75 or SEQ ID NO:28 or SEQ ID NO:64.

14. A cell comprising a modified nucleic acid encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof, preferably a nucleic acid according to claims 1 to 13.

15. The cell according to claim 14, wherein the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell.

16. The cell according to claim 15, wherein the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell.

17. The cell according to anyone of claims 14 to 16, wherein the cell is a cell selected from the list consisting of adventitial fibroblast; alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell; fibromyocyte, goblet cell; ionocyte; lipofibroblast, lymphatic cell, mesothelial cell; myofibroblast; mucous cell, neuroendocrine cell; pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell.

18. The cell according to anyone of claims 14 to 17, wherein the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte; and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof.

19. The cell according to anyone of claims 14 to 18, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte.

20. The cell according to claim 19 wherein the cell is an alveolar macrophage.

21. A pharmaceutical composition comprising the nucleic acid of any one of claims 1-13.

22. The pharmaceutical composition according to claim 21, wherein the nucleic acid is in the form of a lipid nanoparticle (LNP) or a lipidoid nanoparticle (LiNP) formulation.

23. The pharmaceutical composition according to any one of claim 21 or 22, wherein the composition comprises a lipidoid nanoparticle formulation comprising: a) a nucleic acid coding for a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein , b) a cationic lipidoid of formula (b-V), and

c) one or more helper lipid(s), optionally selected from: c1) DPPC, and/or c2) cholesterol, and/or c3) PEG-lipid DMG-PEG2000, and optionally d) a triblock copolymer, preferably, components b) and c1-c3) are present, more preferably they are at the molar ratios of about (4-10):(4-7):(3-6):(0.3-3), preferably about (6-9):(4-7):(3-6):(0.3-3), more preferably about 8:(4-7):(3-6):(0.3-3), even more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively.

24. The pharmaceutical composition according to any one of claims 21 to 23, wherein: a) said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma and/or b) wherein the pharmaceutical composition or polyribonucleotide is administered once to three times a week, preferably three times a week, for at least 1 week, preferably for at least 2 weeks, more preferably for at least 3 weeks and even more preferably for at least 4 weeks, and/or c) wherein the pharmaceutical composition when administered via inhalation comprises in a dose for a treatment day an amount of nucleic acid of about 200 µg to about 15 mg, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day.

25. The nucleic acid according to any one of claims 1 to 13, or the cell according to any of claims 14 to 20, or the pharmaceutical composition of any one of claims 21 to 24 for use as a medicament.

26. A modified nucleic acid encoding GM-CSF, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF or citrullinated or any functional fragments thereof, or the nucleic acid according to any one of claims 1 to 13, or the pharmaceutical composition of any one of claims 21 to 24 or the cell of any one of claims 14 to 20 for use in a method for the treatment or prevention of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency, a GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein related disease or a disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency in a subject or patient.

27. The modified nucleic acid or the pharmaceutical composition or the cell for use according to claim 26, wherein the modified nucleic acid is a polyribonucleotide, preferably an mRNA.

28. The modified nucleic acid or the pharmaceutical composition or the cell for use according to claim 26 or 27, wherein the modified nucleic acid is a low-immunogenic nucleic acid.

29. The modified nucleic acid or the pharmaceutical composition or the cell for use according to claim 28, wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid.

30. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 29, wherein the nucleic acid comprises a chemically modified nucleoside selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof.

31. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 29, wherein the nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine.

32. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 29, wherein the nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1- methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine.

33. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 29, wherein the nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5- Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5-Iodouridine and 2%-5% 5- Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5-Iodocytidine.

34. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 27 to 33, wherein the modified mRNA is a codon optimized GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein , preferably wherein the modified mRNA is codon optimized for expression of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein in a human.

35. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 29, wherein the nucleic acid is as defined in any one of claims 1 to 13.

36. The nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 35, wherein the GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency, the GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein related disease or the disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof.

37. The modified nucleic acid or the pharmaceutical composition or the cell for the use according to claim 36, wherein the disease is PAP, preferably aPAP.

38. The nucleic acid or the pharmaceutical composition or the cell for the use according to any one of claims 26 to 37, wherein the disease to be treated is a PAP related to a defective or deficient GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein production or a defective or deficient GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein receptor function.

39. The nucleic acid or the pharmaceutical composition or the cell for use according to claim 36, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

40. The modified nucleic acid or fragment thereof or the pharmaceutical composition or the cell for use according to anyone of claims 26 to 39, wherein the nucleic acid is produced using an in-vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase.

41. The nucleic acid or the pharmaceutical composition or the cell for use of any one of claims 26 to 40, wherein the nucleic acid, or the cell, or the pharmaceutical composition is administered to the patient in need of treatment, preferably via inhalation.

42. The nucleic acid or the pharmaceutical composition or the cell for use according to any one of claims 26 to 41, wherein the patient in need of treatment is characterized by intraalveolar surfactant accumulation.

43. The nucleic acid or the pharmaceutical composition or the cell for use according to claim 42, wherein the intraalveolar surfactant accumulation is determined by bronchoalveolar lavage fluid turbidity.

44. The nucleic acid or the pharmaceutical composition or the cell for use according to any one of claims 41 to 43, wherein the patient in need of treatment is characterized for being positive to the presence of autoantibodies directed to GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or to GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor, such as antiGM-CSF/antiGM-CSF receptor, anti-synthetase receptor, anti-MDA5 receptor, anti- Scl70 receptor, anti-eIF2B receptor, anti-PM/Scl receptor, anti-Ku receptor, anti-Topo I receptor, anti-Th/To receptor, anti-U11/U12 RNP receptor, anti-U1RNP receptor, anti-RF receptor and/or ACPA receptor autoantibodies or antiGM-CSF/antiGM-CSF receptor, anti- synthetase receptor, anti-MDA5 receptor, anti-Scl70 receptor, anti-eIF2B receptor, anti- PM/Scl receptor, anti-Ku receptor, anti-Topo I receptor, anti-Th/To receptor, anti-U11/U12 RNP receptor, anti-U1RNP receptor, anti-RF receptor and/or ACPA receptor neutralizing antibodies, optionally wherein the patient suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM-CSF/antiGM- CSF receptor, anti-synthetase receptor, anti-MDA5 receptor, anti-Scl70 receptor, anti- eIF2B receptor, anti-PM/Scl receptor, anti-Ku receptor, anti-Topo I receptor, anti-Th/To receptor, anti-U11/U12 RNP receptor, anti-U1RNP receptor, anti-RF receptor and/or ACPA receptor autoantibodies or antiGM-CSF/antiGM-CSF receptor, anti-synthetase receptor, anti-MDA5 receptor, anti-Scl70 receptor, anti-eIF2B receptor, anti-PM/Scl receptor, anti-Ku receptor, anti-Topo I receptor, anti-Th/To receptor, anti-U11/U12 RNP receptor, anti- U1RNP receptor, anti-RF receptor and/or ACPA receptor neutralizing antibodies in the patient.

45. The nucleic acid or the pharmaceutical composition or the cell for use according to any one of claims 42 to 44, wherein the patient in need of treatment receives via inhalation a nucleic acid dose of about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day.

46. A pharmaceutical composition comprising a modified nucleic acid encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof for use in a method for the treatment or prevention of a disease selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., and Plasmodium sp.

47. The pharmaceutical composition according to claim 46, wherein the modified nucleic acid is selected from a polynucleotide DNA or a polynucleotide RNA, preferably wherein said polynucleotide RNA is an mRNA.

48. The pharmaceutical composition according to anyone of claims 46 or 47, wherein the modified nucleic acid comprises a combination of unmodified nucleosides and chemically modified nucleosides.

49. The pharmaceutical composition according to claim 48, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic.

50. The pharmaceutical composition according to claim 48 or 49, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof.

51. The pharmaceutical composition according to claims 46 to 50, wherein the modified nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine.

52. The pharmaceutical composition according to claims 46 to 50, wherein the modified nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1-methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine.

53. The pharmaceutical composition according to claims 46 to 50, wherein the modified nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5- Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5- Iodocytidine.

54. The pharmaceutical composition according to claims 46 to 50, wherein the modified nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ).

55. The pharmaceutical composition according to claims 46 to 54, wherein the modified nucleic acid comprises a nucleic acid sequence, preferably a nucleic acid sequence encoding a GM-CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73.

56. The pharmaceutical composition for use according to anyone of claims 46 to 55, wherein: a) the PAP is autoimmune pulmonary alveolar proteinosis (aPAP) and/or b) the viral infection is influenza, SARS, or Covid, and/or c) the pulmonary fibrosis is idiopathic pulmonary fibrosis

57. The pharmaceutical composition for use according to anyone of claims 46 to 56, wherein the composition comprises: a) a nucleic acid coding for GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein, b) a cationic lipidoid, optionally a lipidoid of formula (b-V), and

c) one or more helper lipid(s), optionally selected from: c1) DPPC, and/or c2) cholesterol, and/or c3) PEG-lipid DMG-PEG2000, and optionally d) a triblock copolymer, optionally, when b), and c1)-c3) are present, they are at the molar ratios of about (4-10):(4- 7):(3-6):(0.3-3), preferably about (6-9):(4-7):(3-6):(0.3-3), more preferably about 8:(4-7):(3- 6):(0.3-3), more preferably about 8 (e.g about 8.0) : about 5 (e.g about 5.3) : about 4 (e.g. about 4.4) : about 1 (e.g. about 0.9), most preferably 8:5.29:4.41:0.88, respectively,, preferably, all b), c1)-c3) and d) compositions are present.

58. The nucleic acid for use according to any one of claims 26 to 45, or the cell for use according to any one of claims 26 to 45, or the pharmaceutical composition for use according to any one of claims 26 to 57, wherein the nucleic acid or the pharmaceutical composition is to be administered by delivery into the respiratory system.

59. The nucleic acid for use according to any one of claims 26 to 45 and 58, or the cell for use of any one of claims 26 to 45 and 58, or the pharmaceutical composition for use of any one of claims 26 to 58, wherein said delivery into the respiratory system is by inhalation.

60. The nucleic acid for use of claim 59, or the cell for use of claim 59, or the pharmaceutical composition for use of claim 59, wherein said inhalation is inhalation of an aerosol comprising said nucleic acid or said pharmaceutical composition.

61. The nucleic acid for use of any one of claims 26 to 45 and 58 to 60, or the cell for use according to any one of claims 26 to 45 and 58 to 60, or the pharmaceutical composition for use according to any one of claims 26 to 60, wherein said nucleic acid, or cell, or pharmaceutical composition is delivered to a target cell or a tissue comprising said target cell, preferably wherein said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is an alveolar epithelial cell, a granulocyte, or an alveolar macrophage.

62. The pharmaceutical composition for the use according to any one of claims 46 to 61, wherein said nucleic acid is as defined in any one of claims 1 to 13.

63. The pharmaceutical composition according to any one of claims 21 to 24 or the pharmaceutical composition for use according to any one of claims 26 to 62 wherein said composition further comprises an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma.

64. The nucleic acid for use of any one of claims 26 to 45 and 58 to 61, or the cell for use according to any one of claims 26 to 45 and 58 to 61, or the pharmaceutical composition for use according to any one of claims 26 to 63, wherein the treatment results in one or more of: (i) dose-dependent increases of GM-CSF level in bronchoalveolar lavage fluid (BALF) in the presence of a PAP phenotype, (ii) improvement of BALF-related endpoints, including reduced turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts, (iii) a shift in the phenotype of macrophages from large, lipid-filled macrophages towards regular-sized macrophages with limited lipid or no lipid content, (iv) activation of GM-CSF downstream genes, (v) efficient STAT5 activation/phosphorylation via autocrine stimulation, (vi) efficient STAT5 activation/phosphorylation in human THP-1 macrophages in comparison to recombinant hGM-CSF, e.g. in presence of hGM-CSF-neutralizing antibodies.

65. Use of the nucleic acid, the expression vector or the pharmaceutical composition according to anyone of the preceding claims in a method of activation and/or expansion of a macrophage, a monocyte and/or a granulocyte.

66. The use according to claim 65, wherein the use is in-vitro or ex-vivo, e.g. wherein the macrophage, the monocyte and/or the granulocyte activation and/or expansion occurs in- vitro or ex-vivo.

67. The use according to any one of claims 65 or 66, wherein the macrophage is an alveolar macrophage and the monocyte is a migrating monocyte.

68. A method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof; wherein the nucleic acid comprises one or more sequences encoding a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof being delivered to and expressed in a target cell comprising a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor (autocrine signaling) or is delivered to and expressed in a neighbor cell to said target cell (paracrine signaling).

69. The method according to claim 68, wherein the modified nucleic acid is selected from a polynucleotide DNA or a polynucleotide RNA, preferably wherein said polynucleotide RNA is an mRNA.

70. The method according to anyone of claims 68 or 69, wherein the modified nucleic acid comprises a combination of unmodified nucleosides and chemically modified nucleosides.

71. The method according to claim 70, wherein the chemically modified nucleoside is selected from nucleosides rendering the nucleic acid low-immunogenic or non-immunogenic.

72. The method according to claim 71, wherein the low-immunogenic nucleic acid shows a decrease in the immune response by at least 30% as compared with an unmodified nucleic acid, preferably at least 50%, or at least 75%, or wherein the low-immunogenic nucleic acid shows a decrease in the immune response by 100%, such as an immune response may be completely prevented, as measured by: a) the binding of the modified nucleic acid to TLR-3, TLR-7, TLR-8, and/or RIG-I, and/or b) levels of TNF-α, IFN-α, IFN-β, IL-8, IL-6, and /or IL-12, in a cell contacted with the modified nucleic acid and compared with a cell contacted with an unmodified nucleic acid.

73. The method according to anyone of claims 70 to 72, wherein the chemically modified nucleoside is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, 2′-O-methyl uridine, 5-iodo-uridine, 5-iodo-citosine and combinations thereof.

74. The method according to anyone of claims 70 to 72, wherein the modified nucleic acid comprises the chemically modified nucleosides 2-thiouridine and 5-methylcytidine, preferably wherein between 5% and 50% of the uridines and cytidines are 2-thiouridine and/or 5-methylcytidine, most preferably 25% 2-Thiouridine and 25% 5-Methylcytidine.

75. The method according to anyone of claims 70 to 72, wherein the modified nucleic acid comprises the chemically modified nucleoside N1-methylpseudouridine, preferably at least 1% N1-methylpseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% N1-methylpseudouridine.

76. The method according to anyone of claims 70 to 72, wherein the modified nucleic acid comprises the chemically modified nucleosides 5-Iodouridine (I5U) and 5-Iodocytidine (I5C), preferably wherein the nucleic acid comprises between 1% and 50% of the chemically modified nucleosides 5-Iodouridine and 5-Iodocytidine, more preferably 20%-40% 5- Iodouridine and 2%-5% 5-Iodocytidine, most preferably 30% 5-Iodouridine and 3% 5- Iodocytidine.

77. The method according to anyone of claims 70 to 72, wherein the modified nucleic acid comprises at least one pseudo uridine (ψ), preferably at least 1% pseudouridine, more preferably at least 10%, even more preferably 50%, most preferably 100% pseudouridine (ψ).

78. The method according to anyone of claims 68 to 77, wherein the modified nucleic acid comprises a nucleic acid sequence, preferably a nucleic acid sequence encoding a GM- CSF protein or a functional fragment thereof, such as a GM-CSF protein comprising an amino acid sequence as shown in SEQ ID NO: 2 or a functional fragment thereof, preferably a nucleic acid sequence having at least 94% identity to SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:27, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:63, SEQ ID NO:72, or SEQ ID NO:73.

79. The method according to anyone of claims 68 to 78, wherein the modified nucleic acid is an mRNA codon optimized for expression of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein, preferably wherein the modified mRNA is codon optimized for expression of a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein in a human.

80. The method according to anyone of claims 68 to 79, wherein the nucleic acid is as defined in any one of claims 1 to 12.

81. The method according to anyone of claims 68 to 80, wherein the GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency, the GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein related disease or the disease caused by a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency is selected from the list consisting of pulmonary alveolar proteinosis (PAP), interstitial lung disease such as pulmonary fibrosis, e.g. idiopathic pulmonary fibrosis, viral infections, such as Influenza and COVID-19, acute respiratory distress syndrome (ARDS), non-tuberculous mycobacterial (NTM) infection, lung cancer, fungal infections caused by Aspergillus sp., such as aspergillosis, fungal sinusitis, otomycosis, keratitis, and onychomycosis, preferably those caused by Aspergillus fumigatus and Aspergillus flavus, infections caused by Mycobacterium tuberculosis, Pseudomonas aeruginosa, Pneumocystis sp., Plasmodium sp., Cryptocuccus sp., Norcardia sp., and combinations thereof.

82. The method according to anyone of claims 68 to 81, wherein the disease is PAP, preferably aPAP.

83. The method according to anyone of claims 68 to 82, wherein the disease to be treated is a PAP related to a defective or deficient GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein production or a defective or deficient GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor function.

84. The method according to claim 81, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

85. The method according to anyone of claims 68 to 84, wherein the nucleic acid is produced using an in-vitro polymerase synthesis process, preferably wherein the nucleic acid is an mRNA and/or the polymerase is a T7 polymerase.

86. The method according to anyone of claims 68 to 85, wherein the nucleic acid is administered by delivery into the respiratory system.

87. The method according to claim 86, wherein the nucleic acid is administered to the subject via inhalation.

88. The method according to claim 87, wherein said inhalation is inhalation of an aerosol comprising said nucleic acid.

89. The method according to anyone of claims 68 to 88, wherein a nucleic acid dose of about 200 µg to about 15 mg in each treatment day, preferably about 1 mg to about 10 mg in each treatment day, more preferably about 4.5 mg of nucleic acid in each treatment day is administered to the subject via inhalation.

90. The method according to anyone of claims 68 to 89, wherein the subject is characterized by intraalveolar surfactant accumulation.

91. The method according to claim 90, wherein the intraalveolar surfactant accumulation is determined by bronchoalveolar lavage fluid turbidity.

92. The method according to anyone of claims 68 to 91, wherein the subject is characterized for being positive to the presence of autoantibodies directed to GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or to the GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor, such as antiGM-CSF/antiGM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor autoantibodies or GM-CSF/GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor neutralizing antibodies, optionally wherein the patient suffers from autoimmune PAP and the autoimmune PAP is caused by or partially caused by the presence of antiGM- CSF/antiGM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor autoantibodies or GM-CSF/GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor neutralizing antibodies in the patient.

93. The method according to anyone of claims 68 to 92, wherein said nucleic acid, is delivered to a target cell or a tissue comprising said target cell, preferably wherein said target cell is a cell selected from the list consisting of a respiratory airway epithelial cell, an immune cell, or both, more preferably said target cell is an alveolar epithelial cell, a granulocyte, or an alveolar macrophage.

94. The method according to anyone of claims 68 to 93, wherein the target cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, a migrating monocyte; and/or b) an alveolar cell, preferably an alveolar epithelial cell, a goblet cell, a ciliate cell and/or combinations thereof.

95. The method according to any one of claims 68 to 94, wherein GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein is expressed in the target cell for at least 6 hours, preferably for at least 12 hours; more preferably for at least 24 hours.

96. The method according to any one of claims 68 to 95, wherein the method further comprises administering an mRNA encoding one or more further cytokines, preferably said cytokine is interferon lambda or interferon gamma.

97. The method according to any one of claims 68 to 96, wherein the method results in one or more of: (i) dose-dependent increases of GM-CSF level in bronchoalveolar lavage fluid (BALF) in the presence of a PAP phenotype, (ii) improvement of BALF-related endpoints, including reduced turbidity, reduction of surfactant protein level, reduction of cellularity and reduction of macrophage counts, (iii) a shift in the phenotype of macrophages from large, lipid-filled macrophages towards regular-sized macrophages with limited lipid or no lipid content, (iv) activation of GM-CSF downstream genes, (v) efficient STAT5 activation/phosphorylation via autocrine stimulation, (vi) efficient STAT5 activation/phosphorylation in human THP-1 macrophages in comparison to recombinant hGM-CSF, e.g. in presence of hGM-CSF-neutralizing antibodies.

98. A method for restoring a ligand-receptor interaction between a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor in a target cell wherein the method comprises the steps of: a) delivering a nucleic acid encoding one or more of said GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof into a target cell comprising said GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor or into a neighboring cell to said target cell, and optionally b) expressing the nucleic acid in said target cell and allowing GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein to act in an autocrine manner, or alternatively expressing GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein in said neighboring cell, and/or allowing GM- CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein to act in a paracrine manner, and optionally c) allowing the GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein to interact with its respective receptor and thereby restoring the interaction between the ligand GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein and its respective receptor.

99. The method of claim 98, wherein said GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein once expressed: a) binds to a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor in an external cell membrane, and/or b) binds to a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor already intracellularly, optionally in an intracellular membrane.

100. The method according to any one of claims 98 or 99, wherein GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein acts in an autocrine manner, optionally act in an autocrine manner in a granulocyte or a macrophage, preferably an alveolar macrophage.

101. The method of anyone of claims 98 to 100, wherein the method occurs ex-vivo or in vitro.

102. A kit comprising the nucleic acid of any one of claim 1 to 13, or the cell of any one of claims 14 to 20, or the pharmaceutical composition of any one of claims 21 to 24, and a delivery device, preferably wherein the delivery device is a nebulizer.

103. A method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency in a subject in need thereof, the method comprising, obtaining a cell from the subject and/or from a donor and contacting the cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof, and administering the cell into a subject.

104. The method according to claim 103, wherein the cell is autologous to the subject, such as that the cell is administered to the same subject as it is obtained from.

105. The method according to claim 103, wherein the cell is allogeneic to the subject, such as that the cell is administered to another subject as it is obtained from.

106. An ex vivo or in vitro method for expressing a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein in a cell, the method comprising contacting a cell with a modified nucleic acid, wherein the modified nucleic acid is a polynucleotide comprising one or more sequences encoding GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein or any functional fragments thereof.

107. The method according to claim 106, wherein the cell is GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficient, e.g. does not produce a sufficient amount of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein when compared to a wild type cell.

108. The method according to any one of claims 103 to 107, wherein the cell is a cell selected from the list consisting of a respiratory airway cell, an epithelial cell, a skin cell and/or an immune cell.

109. The method according to claim 108, wherein the respiratory airway cell is selected from the list consisting of a proximal airway cell, a distal airway cell, or an alveolar cell.

110. The method according to any one of claims 103 to 109, wherein the cell is a cell selected from the list consisting of adventitial fibroblast, alveolar fibroblast, airway smooth muscle cell, basal cell, differentiating basal cell, proliferating basal cell, proximal basal cell, bronchial vessel cell, general capillary cell, capillary aerocyte, capillary intermediate cell, ciliated cell, proximal ciliated cell; fibromyocyte, goblet cell, ionocyte, lipofibroblast, lymphatic cell, mesothelial cell, myofibroblast; mucous cell, neuroendocrine cell; pericyte, serous cell, vascular smooth muscle cell, a mononuclear immune cell, a resident immune cell and/or a migrating immune cell.

111. The method according to any one of claims 103 to 110, wherein the cell is: a) a resident or a migrating immune cell, preferably a macrophage, a resident granulocyte, or a migrating monocyte, and/or b) an alveolar cell, preferably a goblet cell, a ciliate cell and/or combinations thereof.

112. The method according to any one of claims 103 to 111, wherein the cell is an alveolar macrophage (AM), an interstitial macrophage (IM), a granulocyte and/or a migrating monocyte.

113. The method according to claim 112, wherein the cell is an alveolar macrophage.

114. The method according to anyone of claims 103 to 113, wherein the nucleic acid is as defined in any one of claims 1 to 13.

115. A chemically modified mRNA encoding one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof for use in a method of treating a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated protein deficiency, optionally comprising restoring a ligand-receptor interaction between a GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and a GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor in a target cell, wherein: a) the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof is to be delivered into a target cell comprising said GM-CSF receptor, synthetase receptor, MDA5 receptor, Scl70 receptor, eIF2B receptor, PM/Scl receptor, Ku receptor, Topo I receptor, Th/To receptor, U11/U12 RNP receptor, U1RNP receptor, RF receptor and/or citrullinated protein receptor or into a neighboring cell to said target cell, and optionally b) wherein the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof is to be expressed in said target cell and allowing the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein to act in an autocrine manner, or alternatively wherein the chemically modified mRNA encoding one or more of GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein or any active fragments thereof is to be expressed in said neighboring cell, and/or allowing the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein to act in a paracrine manner, and optionally c) the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein is to be allowed to interact with its respective receptor and thereby restoring the interaction between the one or more GM-CSF, synthetase, MDA5, Scl70, eIF2B, PM/Scl, Ku, Topo I, Th/To, U11/U12 RNP, U1RNP, RF and/or citrullinated ligand protein and its respective receptor.