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WO2022195042A1 - Protéine ayant une fonction de hdgf (facteur de croissance dérivé de l'hépatome) pour une utilisation dans le traitement et la prévention de maladies neurodégénératives - Google Patents

Protéine ayant une fonction de hdgf (facteur de croissance dérivé de l'hépatome) pour une utilisation dans le traitement et la prévention de maladies neurodégénératives Download PDF

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WO2022195042A1
WO2022195042A1 PCT/EP2022/057062 EP2022057062W WO2022195042A1 WO 2022195042 A1 WO2022195042 A1 WO 2022195042A1 EP 2022057062 W EP2022057062 W EP 2022057062W WO 2022195042 A1 WO2022195042 A1 WO 2022195042A1
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hdgf
protein
nucleic acid
seq
mice
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Rüdiger KLEIN
Irina DUDANOVA
Sara GUTIERREZ-ANGEL
Kerstin VOELKL
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • HDGF hepatoma-derived growth factor
  • the present invention relates to a protein having HDGF (hepatoma-derived growth factor) function or a nucleic acid molecule capable of expressing a protein having HDGF function for use in preventing or treating neurodegenerative diseases.
  • the present invention also relates to a method for diagnosing neurodegenerative disease in a subject, comprising i) detecting the expression level of HDGF in a sample obtained from said subject, and ii) comparing said expression level of HDGF with the expression level of HDGF in a sample obtained from a healthy subject(s) or with a predetermined standard expression level, wherein a greater that 2-fold downregulation is indicative for neurodegenerative disease in the subject.
  • Neurodegenerative diseases are diseases characterized by progressive neuronal cell death.
  • Classical examples include hereditary triplet repeat expansion disorders such as Huntington’s disease (HD) and synucleinopathies, including Parkinson’s disease (PD).
  • HD Huntington’s disease
  • PD Parkinson’s disease
  • Huntington is a fatal hereditary neurodegenerative disorder that manifests with motor, psychiatric, and cognitive symptoms (Tabrizi et al., 2020). It is caused by a CAG repeat expansion in exon 1 of the Huntingtin gene (The Huntington's Disease Collaborative Research Group, 1993), resulting in translation of the mutant Huntingtin (mHTT) protein with an elongated glutamine (polyQ) tract. Neuropathologically, HD is characterized by formation of intranuclear mHTT inclusion bodies (IBs) and by severe neurodegeneration, especially in the striatum and neocortex (DiFiglia et al., 1997).
  • IBs intranuclear mHTT inclusion bodies
  • BDNF brain-derived neurotrophic factor
  • TrkB and p75NTR small molecule ligands of the BDNF receptors TrkB and p75NTR
  • Ciliary neurotrophic factor was also shown to be protective in HD mouse and primate models (Anderson et al., 1996; Emerich et al., 1997; Mittoux et al., 2000).
  • Fibroblast growth factor 9 FGF9 improves survival of striatal cells with HTT mutation in cell culture (Yusuf et al., 2018).
  • FGF9 Fibroblast growth factor 9
  • HDGF hepatoma-derived growth factor
  • HDGF neuroprotective properties of HDGF have so far only been demonstrated with respect to retinal ganglion cell survival in an optic nerve transection model (Hollander et al., 2012), and facial motor neuron survival after facial nerve section (Marubuchi, 2006).
  • HDGF was originally identified in the supernatant of a human hepatoma cell line (Nakamura et al., 1994). It stimulates cell proliferation both when it is overexpressed in cell lines as well as applied exogenously (Everett et al., 2000; Everett et al., 2004; Mao et al., 2008; Nakamura et al., 1994; Oliver and Al-Awqati, 1998). HDGF has so far mostly been investigated in different types of cancer.
  • the present invention relates in a first aspect to a protein having HDGF (hepatoma-derived growth factor) function or a nucleic acid molecule capable of expressing a protein having HDGF function for use in preventing or treating neurodegenerative diseases.
  • HDGF hepatoma-derived growth factor
  • HDGF ameliorates mHTT- related phenotypes in neuron-like cells, primary neurons and in a HD mouse model, while HDGF deficiency aggravates disease progression.
  • HDGF levels is a novel therapeutic strategy to treat subjects with neurodegenerative diseases.
  • the protein or the nucleic acid molecule is for use in preventing or treating Huntington’s disease or a synucleinopathy.
  • protein as used herein is used interchangeably with the term (poly)peptide.
  • Poly)peptides describe a group of molecules which comprise the group of peptides consisting of up to 30 amino acids, as well as the group of polypeptides consisting of more than 30 amino acids.
  • protein also refers to chemically or post-translationally modified proteins.
  • nucleic acid molecule is used interchangeably with the term “nucleotide sequence” and relates to polynucleotides including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is understood that the term “RNA” as used herein comprises all forms of RNA including mRNA.
  • neurodegenerative disease as described herein is interchangeably used with the term “neurodegenerative disorder” and relates to a disease characterized by a progressive decline in the structure, activity, and/or function of neural tissue, including brain tissue.
  • Huntingtins disease relates to an inheritable neurological disease cause by a trinucleotide repeat expansion in the gene coding for the Huntingtin protein.
  • synucleinopathy as used herein relates to a group of neurodegenerative diseases characterized by aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease, dementia with Lewy bodies (DLB) and multiple systems atrophy (MSA).
  • Parkinson's disease dementia with Lewy bodies (DLB)
  • MSA multiple systems atrophy
  • treating neurodegenerative diseases includes treatment of existing neurodegenerative diseases.
  • preventing neurodegenerative diseases includes the prevention of the onset of neurodegenerative diseases or of one or more symptoms associated with neurodegenerative diseases and the prophylactic treatment of those at risk of developing neurodegenerative diseases.
  • the term “protein having HDGF function” relates to a protein having all of the following functions: HDGF has mitogenic and growth-promoting activity for several cell types. For example, it induces a 100% increase in the proliferation of vascular smooth muscle cells when applied for 72 hours at the concentration of 1 pg/ml (Everett et al., 2000). It also increases migration of human pulmonary microvascular endothelial cells by 2-fold when applied for 24 hours, and promotes the growth of blood vessels in an in vitro angiogenesis assay by about 50% when applied at the concentration of 190 ng for 4 days (Everett et al., 2004).
  • HDGF vascular endothelial growth factor
  • mHTT mutant huntingtin
  • a-synuclein toxicity in primary neurons
  • the protein or the nucleic acid molecule for use in preventing or treating neurodegenerative diseases acts by ameliorating mutant huntingtin and/or or a-synuclein toxicity in primary neurons.
  • Methods to assess mHTT and/or a-synuclein toxicity in primary neurons include, for example, the quantification of mHTT inclusion bodies (IBs) to quantify mHTT aggregation, the determination of cell death rate in cells by counting immunopositive cells for an apoptotic marker and assessing nuclear integrity, or quantification of cell viability by an LDH or MTT assay.
  • IBs mHTT inclusion bodies
  • the R6/2 mouse model was used (Mangiarini et al., 1996).
  • the transgenic R6/2 mice express exon 1 of human mHTT.
  • This model develops HD-like symptoms, including motor and cognitive deficits as well as decreased body weight.
  • R6/2 mice injected with a control virus not expressing HDGF showed markedly impaired locomotion in the open field compared to WT (wild type) littermates with a reduction in the distance traveled as well as in the rearing frequency.
  • WT wild type
  • the protein or the nucleic acid molecule for use in preventing or treating neurodegenerative diseases have the function of improving motor defects and/or reducing mutant Huntingtin inclusion bodies in the striatum.
  • the protein for use in preventing or treating neurodegenerative diseases has an amino acid sequence comprising SEQ ID NO:1 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:1.
  • sequence identity of the amino acid sequence according to above-mentioned preferred embodiment of the first aspect of the invention is with increased preference at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5% identical to SEQ ID NO:1 and is most preferably 100% identical to SEQ ID NO:1.
  • SEQ ID NO:1 represents the amino acid sequence of isoform 1 (also referred to in the art as isoform a) of human hepatoma-derived growth factor (HDGF). Within the sequence identity level of at least 95% of SEQ ID NO:1 , other isoforms of human HDGF, such as isoforms 2 and 3 (also referred to in the art as isoforms b and c) are specifically also included.
  • percent sequence identity relates to the percentage of residues in a nucleic acid sequence or an amino acid sequence that are identical to a reference sequence when the two sequences are optimally aligned.
  • Nucleotide and amino acid sequence analysis and alignment in connection with the present invention are preferably carried out using the NCBI BLAST algorithm (Stephen F. Altschul, Thomas L. Madden, Alejandro A. Schaffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), Nucleic Acids Res. 25:3389-3402).
  • BLAST can be used for nucleotide sequences (nucleotide BLAST) and amino acid sequences (protein BLAST). The skilled person is aware of additional suitable programs to align nucleic acid sequences.
  • the nucleic acid molecule for use in preventing or treating neurodegenerative diseases comprises the nucleotide sequence of SEQ ID NO:2 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:2.
  • sequence identity of the nucleotide sequence according to above-mentioned preferred embodiment of the first aspect of the invention is with increased preference at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5% identical to SEQ ID NO:2 and is most preferably 100% identical to SEQ ID NO:2.
  • the thymidine residues of SEQ ID NO:2 are replaced by uridine residues.
  • the nucleic acid molecule is the mRNA naturally obtained by transcription of the DNA molecule represented by SEQ ID NO:2 or an mRNA molecule having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% and most preferably 100% sequence identity to said natural mRNA.
  • the protein for use in preventing or treating neurodegenerative diseases is a cytosolic version of HDGF, comprising the amino acid sequence of SEQ ID NO:3 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:3.
  • sequence identity of the amino acid sequence according to above-mentioned preferred embodiment of the first aspect of the invention is with increased preference at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5% identical to SEQ ID NO: 3 and is most preferably 100% identical to SEQ ID NO:3.
  • the nucleic acid molecule for use in preventing or treating neurodegenerative diseases expresses a cytosolic version of HDGF and comprises the nucleotide sequence of SEQ ID NO:4 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:4.
  • SEQ ID NO:4 represents the nucleotide sequence of a cytosolic version of HDGF, wherein 12 point mutations have been introduced into the two nuclear localization sequences of HDGF and wherein a nuclear export sequence has been added to its C-terminus (see Figure 5).
  • sequence identity of the nucleotide sequence according to above-mentioned preferred embodiment of the first aspect of the invention is with increased preference at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5% identical to SEQ ID NO:4 and is most preferably 100% identical to SEQ ID NO:4.
  • the thymidine residues of SEQ ID NO:4 are replaced by uridine residues.
  • the nucleic acid molecule is the mRNA naturally obtained by transcription of the DNA molecule represented by SEQ ID NO:4 or an mRNA molecule having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% and most preferably 100% sequence identity to said natural mRNA.
  • SEQ ID NO:3 represents the amino acid sequence of a cytosolic version of HDGF and SEQ ID NO:4 represents the nucleotide sequence of a cytosolic version of HDGF.
  • cytosolic versions may be used in accordance with the first aspect of the invention.
  • the nucleic acid molecule for use in preventing or treating neurodegenerative diseases is comprised in an expression vector.
  • expression vector as used herein relates to a DNA molecule that may be used to transfer and express a gene of interest into a cell. Once the expression vector is inside the cell, the (poly)peptide that is encoded by the gene of interest is produced by the cellular transcription and translation machinery ribosomal complexes.
  • the nucleic acid molecules inserted into the vector can e.g. be synthesized by standard methods or isolated from natural sources. Ligation of the coding sequences to transcriptional regulatory elements and/or to other amino acid encoding sequences can also be carried out using established methods.
  • the expression vector will typically comprise transcriptional regulatory elements (parts of an expression cassette) that ensure expression in eukaryotic cells. Transcriptional regulatory elements (parts of an expression cassette) ensuring expression in eukaryotic cells are well known to those skilled in the art.
  • These elements comprise regulatory sequences ensuring the initiation of transcription (e. g., translation initiation codon, promoters, such as naturally-associated or heterologous promoters, internal ribosomal entry sites (IRES) (Owens, Proc. Natl. Acad. Sci. USA 98 (2001), 1471-1476) and optionally poly-A signals ensuring termination of transcription and stabilization of the transcript.
  • the expression vector may contain a tissue- specific or cell-specific promoter to control the location of expression. Additional regulatory elements may include transcriptional as well as translational enhancers.
  • the nucleic acid sequence of SEQ ID NO:2 or SEQ ID NO:4 or a nucleotide sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% and most preferably 100% sequence identity to SEQ ID NO:2 or SEQ ID NO:4 may be operatively linked to such expression control sequences allowing expression in eukaryotic cells.
  • the vector may further comprise nucleic acid sequences encoding secretion signals as further regulatory elements. Such sequences are well known to the person skilled in the art.
  • leader sequences capable of directing the expressed polypeptide to a cellular compartment may be added to the coding sequence of the invention.
  • Such leader sequences are well known in the art.
  • self-cleaving peptide sequences or other sequences allowing bi- or multicistronic expression may be added. Such sequences are well known in the art.
  • the expression vector may be any vector system including, but not limited to, plasmid vectors, retroviral vectors, lentiviral vectors, adenovirus vectors, poxvirus vectors, herpesvirus vectors and adeno- associated virus vectors.
  • the expression vector is an AAV viral vector.
  • AAV viral vector relates to a vector derived from an adeno-associated virus (AAV) serotype.
  • AAV is a non-enveloped virus that can be engineered to deliver DNA to target cells and has attracted a significant amount of attention in the field, especially in clinical- stage experimental therapeutic strategies.
  • the ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies (for review, Naso et al. (2017), BioDrugs; 31(4): 317-334.).
  • the AAV viral vector may be selected from the serotype of one or more of: AAV1 , AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9 and AAV10.
  • the AAV viral vector is AAV8.
  • AAV8 was found to provide the best and most wide-spread neuronal transduction in the mouse brain.
  • the expression vector will typically be formulated into a pharmaceutical composition.
  • the term “pharmaceutical composition” relates to a composition for administration to a subject, preferably a human subject.
  • the pharmaceutical composition may, optionally, comprise further molecules capable of altering the characteristics of the protein or nucleic acid molecule of the invention thereby, for example, stabilizing, modulating and/or activating their function.
  • the composition may be in solid, liquid or gaseous form and may be, inter alia, in the form of (a) powder(s), (a) tablet(s), (a) solution(s) or (an) aerosol(s).
  • the pharmaceutical composition may, optionally and additionally, comprise a pharmaceutically acceptable carrier.
  • Suitable pharmaceutical carriers include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, organic solvents including DMSO etc.
  • Compositions comprising such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to the subject at a suitable dose.
  • the dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the subject's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. The therapeutically effective amount for a given situation will readily be determined by routine experimentation and is within the skills and judgement of the ordinary clinician or physician.
  • In vivo delivery can be achieved, for example, by systemic administration, i.e. intravenous, intraperitoneal, intracardial, intramuscular, intrathecal, subdermal, and/or intracranial administration.
  • systemic administration i.e. intravenous, intraperitoneal, intracardial, intramuscular, intrathecal, subdermal, and/or intracranial administration.
  • administration into the central nervous system including but not limited to direct injection into the cerebral ventricles, the brain or spinal cord.
  • One or more areas of the brain may be targeted, including but not limited to the striatum and/or the cortex.
  • the protein or the nucleic acid molecule for use in preventing or treating neurodegenerative diseases is to be administered into the brain or brain ventricles.
  • the protein or the nucleic acid molecule for use in preventing or treating neurodegenerative diseases is to be administered intrastriatally or into the lateral ventricle(s) of the brain.
  • the protein or nucleic acid molecule such as a naked mRNA (in addition to the expression vector as described above) for use in preventing or treating neurodegenerative disease will typically be formulated in a pharmaceutical composition.
  • HDGF levels were found to directly correlate with mHTT- and a-synuclein-related phenotypes. Hence, a downregulation of the levels of HDGF is indicative of neurodegenerative diseases. Thus, determining the expression levels of HDGF can be expected to be of prognostic value for diagnosing neurodegenerative diseases in a subject. The detection and comparison of HDGF levels may be combined with further diagnostic markers for neurodegenerative diseases in order to enhance the confidence of the diagnostic method.
  • the present invention relates to a method for diagnosing neurodegenerative disease in a subject, comprising i) detecting the expression level of HDGF in a sample obtained from said subject, and ii) comparing said expression level of HDGF with the expression level of HDGF in a sample obtained from healthy subjects or with a predetermined standard expression level, wherein a greater than 2-fold downregulation is indicative for neurodegenerative disease in the subject.
  • sample designates a body fluid sample or a tissue sample.
  • the body fluid sample is preferably selected from blood, serum, plasma, saliva or cerebrospinal fluid.
  • the sample is a cerebrospinal fluid sample.
  • the sample is a brain tissue sample.
  • the brain tissue sample comprises preferably cortical tissue.
  • the “subject” as referred to herein relates to mammals. Human subjects are the most preferred.
  • detecting the expression level of HDGF means determining the amount of HDGF protein and/or mRNA in a sample.
  • HDGF is downregulated in a sample, if the amount of HDGF protein and/or mRNA is significantly lower as compared to the amount of HDGF protein and/or mRNA in a control sample obtained from a healthy subject(s) or with a predetermined standard expression level.
  • the greater than 2-fold downregulation is with increasing preference greater than 3-fold downregulation, greater than 4-fold downregulation, greater than 5-fold downregulation, greater than 6-fold downregulation, greater than 7-fold downregulation and greater than 8-fold downregulation.
  • the higher thresholds for downregulation may increase the reliability of the method of the third aspect of the invention.
  • the method according to the second aspect of the invention preferably encompasses detecting the expression level of HDGF protein of SEQ ID NO:1 and/or HDGF mRNA encoding said HDGF protein in a sample obtained from said subject, and comparing said expression level of HDGF with the expression level of HDGF protein of SEQ ID NO:1 and/or HDGF mRNA encoding said HDGF protein in a sample obtained from healthy subjects or with a predetermined standard expression level.
  • the method according to the second aspect of the invention may also encompass detecting and comparing the expression level of HDGF protein or HDGF mRNA encoding said HDGF protein being with increased preference at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% and most preferably 100% identical to SEQ ID NO: 1 or SEQ ID NO: 2, respectively, wherein SEQ ID NO:2 represents the DNA sequence encoding said HDGF mRNA.
  • the expression level in the samples can be quantified by any suitable means and methods available from the art. In general, relative and absolute quantification means and methods can be used. In absolute quantification no known standards and controls are needed. The expression level can be directly quantified. As well-known in the art, absolute quantification may rely on a predetermined standard curve. In relative quantification the expression level is quantified relative to a reference (such as known control expression levels). Also, in the absence of controls, one can relatively quantify the expression level when comparing e.g. fluorescence intensities.
  • Methods to measure protein (i.e., (poly)peptide) expression levels include, but are not limited to: Western blot, immunoblot, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immune-precipitation, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, liquid chromatography mass spectrometry (LC-MS), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), mass spectrometry, microcytometry, microarray, microscopy, fluorescence activated cell sorting (FACS), flow cytometry, and assays based on a property of the protein including but not limited to DNA binding, ligand binding, or interaction with other protein partners.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • immune-precipitation immune-precipitation
  • surface plasmon resonance chemilum
  • antibody mimetics refers to compounds which, like antibodies, can specifically bind antigens, such as the HDGF protein of SEQ ID NO: 1 or SEQ ID NO:3 in the present case, but which are not structurally related to antibodies.
  • Antibody mimetics are usually artificial peptides or proteins with a molar mass of about 3 to 20 kDa.
  • an antibody mimetic may be selected from the group consisting of affibodies, adnectins, anticalins, DARPins, avimers, nanofitins, affilins, Kunitz domain peptides, Fynomers®, trispecific binding molecules and prododies. These polypeptides are well known in the art and are described in further detail herein below.
  • affibody refers to a family of antibody mimetics which is derived from the Z-domain of staphylococcal protein A. Structurally, affibody molecules are based on a three- helix bundle domain which can also be incorporated into fusion proteins. In itself, an affibody has a molecular mass of around 6kDa and is stable at high temperatures and under acidic or alkaline conditions. Target specificity is obtained by randomisation of 13 amino acids located in two alpha- helices involved in the binding activity of the parent protein domain (Feldwisch J, Tolmachev V.; (2012) Methods Mol Biol. 899:103-26).
  • adnectin (also referred to as “monobody”), as used herein, relates to a molecule based on the 10th extracellular domain of human fibronectin III (10Fn3), which adopts an Ig-like b- sandwich fold of 94 residues with 2 to 3 exposed loops, but lacks the central disulphide bridge (Gebauer and Skerra (2009) Curr Opinion in Chemical Biology 13:245-255).
  • Adnectins with the desired target specificity, i.e. against HDGF can be genetically engineered by introducing modifications in specific loops of the protein.
  • anticalin refers to an engineered protein derived from a lipocalin (Beste G, Schmidt FS, Stibora T, Skerra A. (1999) Proc Natl Acad Sci U S A. 96(5): 1898-903; Gebauer and Skerra (2009) Curr Opinion in Chemical Biology 13:245-255).
  • Anticalins possess an eight-stranded b-barrel which forms a highly conserved core unit among the lipocalins and naturally forms binding sites for ligands by means of four structurally variable loops at the open end.
  • Anticalins although not homologous to the IgG superfamily, show features that so far have been considered typical for the binding sites of antibodies: (i) high structural plasticity as a consequence of sequence variation and (ii) elevated conformational flexibility, allowing induced fit to targets with differing shape.
  • DARPin refers to a designed ankyrin repeat domain (166 residues), which provides a rigid interface arising from typically three repeated b-turns. DARPins usually carry three repeats corresponding to an artificial consensus sequence, wherein six positions per repeat are randomised. Consequently, DARPins lack structural flexibility (Gebauer and Skerra, 2009).
  • avimer refers to a class of antibody mimetics which consist of two or more peptide sequences of 30 to 35 amino acids each, which are derived from A-domains of various membrane receptors and which are connected by linker peptides. Binding of target molecules occurs via the A-domain and domains with the desired binding specificity, i.e. for HDGF, and can be selected, for example, by phage display techniques.
  • the binding specificity of the different A-domains contained in an avimer may but does not have to be identical (Weidle UH, et al., (2013), Cancer Genomics Proteomics; 10(4): 155-68).
  • Nanofitin is an antibody mimetic protein that is derived from the DNA binding protein Sac7d of Sulfolobus acidocaldarius. Nanofitins usually have a molecular weight of around 7kDa and are designed to specifically bind a target molecule, such as e.g. HDGF, by randomising the amino acids on the binding surface (Mouratou B, Behar G, Paillard-Laurance L, Colinet S, Pecorari F refrain (2012) Methods Mol Biol.; 805:315-31).
  • a target molecule such as e.g. HDGF
  • affilin refers to antibody mimetics that are developed by using either gamma-B crystalline or ubiquitin as a scaffold and modifying amino-acids on the surface of these proteins by random mutagenesis. Selection of affilins with the desired target specificity, i.e. against HDGF, is effected, for example, by phage display or ribosome display techniques. Depending on the scaffold, affilins have a molecular weight of approximately 10 or 20kDa. As used herein, the term affilin also refers to di- or multimerised forms of affilins (Weidle UH, et al., (2013), Cancer Genomics Proteomics; 10(4): 155-68).
  • a “Kunitz domain peptide” is derived from the Kunitz domain of a Kunitz-type protease inhibitor such as bovine pancreatic trypsin inhibitor (BPTI), amyloid precursor protein (APP) or tissue factor pathway inhibitor (TFPI).
  • BPTI bovine pancreatic trypsin inhibitor
  • APP amyloid precursor protein
  • TFPI tissue factor pathway inhibitor
  • Kunitz domains have a molecular weight of approximately 6kDA and domains with the required target specificity, i.e. against HDGF, can be selected by display techniques such as phage display (Weidle et al., (2013), Cancer Genomics Proteomics; 10(4): 155-68).
  • Fynomer® refers to a non-immunoglobulin-derived binding polypeptide derived from the human Fyn SH3 domain.
  • Fyn SH3-derived polypeptides are well-known in the art and have been described e.g. in Grabulovski et al. (2007) JBC, 282, p. 3196-3204, WO 2008/022759, Bertschinger et al (2007) Protein Eng Des Sel 20(2):57-68, Gebauer and Skerra (2009) Curr Opinion in Chemical Biology 13:245-255, or Schlatter et al. (2012), MAbs 4:4, 1-12).
  • probody refers to a protease-activatable antibody prodrug.
  • a probody consists of an authentic IgG heavy chain and a modified light chain.
  • a masking peptide is fused to the light chain through a peptide linker that is cleavable by tumor-specific proteases. The masking peptide prevents the probody binding to healthy tissues, thereby minimizing toxic side effects.
  • RNA-seq RNA-sequencing
  • RNA-seq Stark, Grzelak & Hadfield, Nature Reviews Genetics (2019) 20:631-656
  • northern blotting and in situ hybridization e.g., Parker and Barnes, Meth. Mol.
  • RNAse protection assays e.g., Hod, Biotechniques, 13:852-854, 1992
  • PCR-based methods such as reverse transcription polymerase chain reaction (RT-PCR) (Weis et al., Trends in Genetics, 8:263-264, 1992) and real time quantitative PCR, also referred to as qRT-PCR.
  • RT-PCR reverse transcription polymerase chain reaction
  • qRT-PCR real time quantitative PCR
  • antibodies may be employed that can recognize specific mRNA.
  • Representative methods for sequencing-based gene expression analysis include Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS).
  • RNA isolation can be performed using a purification kit, buffer set and protease obtained from commercial manufacturers, such as Qiagen, according to the manufacturer's instructions.
  • Other commercially available RNA isolation kits include MASTERPURETM Complete DNA and RNA Purification Kit (EPICENTRETM Biotechnologies) and Paraffin Block RNA Isolation Kit (Ambion, Inc.).
  • cDNA obtained from reverse transcription of total RNA is spiked with a synthetic DNA molecule (competitor), which matches the targeted cDNA region in all positions, except a single base, and serves as an internal standard.
  • the cDNA/competitor mixture is amplified by standard PCR and is subjected to a post-PCR shrimp alkaline phosphatase (SAP) enzyme treatment, which results in the dephosphorylation of the remaining nucleotides.
  • SAP post-PCR shrimp alkaline phosphatase
  • the PCR products from the competitor and cDNA are subjected to primer extension, which generates distinct mass signals for the competitor- and cDNA-derived PCR products.
  • these products are dispensed on a chip array, which is pre-loaded with components needed for analysis with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis.
  • MALDI-TOF matrix-assisted laser desorption ionization time-of-flight
  • the cDNA present in the reaction is then quantified by analyzing the ratios of the peak areas in the mass spectrum generated. For further details see, e.g., Ding and Cantor, Proc. Natl. Acad. ScL USA, 100:3059-3064, 2003.
  • RNA expression includes, for example, differential display (Liang and Pardee, Science, 257:967-971, 1992); amplified fragment length polymorphism (Kawamoto et al., Genome Res., 12:1305-1312, 1999); BEAD ARRAYTM technology (lllumina, San Diego, CA, USA; Oliphant et al., Discovery of Markers for Disease (Supplement to Biotechniques), June 2002; Ferguson et al., Anal.
  • differential display Liang and Pardee, Science, 257:967-971, 1992
  • amplified fragment length polymorphism Kawamoto et al., Genome Res., 12:1305-1312, 1999
  • BEAD ARRAYTM technology lllumina, San Diego, CA, USA
  • Oliphant et al. Discovery of Markers for Disease (Supplement to Biotechniques), June 2002; Ferguson et al., Anal.
  • Differential gene expression also can be determined using microarray techniques.
  • specific binding partners such as probes (including cDNAs or oligonucleotides) specific for RNAs of interest or antibodies specific for proteins of interest are plated, or arrayed, on a microchip substrate.
  • the microarray is contacted with a sample containing one or more targets (e.g., mRNA or protein) for one or more of the specific binding partners on the microarray.
  • the arrayed specific binding partners form specific detectable interactions (e.g., hybridize or specifically bind to) their cognate targets in the sample of interest.
  • Serial analysis of gene expression is a method that allows the simultaneous and quantitative analysis of a large number of gene transcripts, without the need of providing an individual hybridization probe for each transcript.
  • SAGE Serial analysis of gene expression
  • a short sequence tag (about 10-14 bp) is generated that contains sufficient information to uniquely identify a transcript, provided that the tag is obtained from a unique position within each transcript. Then, many transcripts are linked together to form long serial molecules, that can be sequenced, revealing the identity of the multiple tags simultaneously.
  • the expression pattern of any population of transcripts can be quantified by determining the abundance of individual tags, and identifying the gene corresponding to each tag (see, e.g., Velculescu et al., Science, 270:484-487, 1995, and Velculescu et al., Cell, 88:243-51, 1997).
  • MPSS massively parallel signature sequencing
  • each embodiment mentioned in a dependent claim is combined with each embodiment of each claim (independent or dependent) said dependent claim depends from.
  • a dependent claim 2 reciting 3 alternatives D, E and F and a claim 3 depending from claims 1 and 2 and reciting 3 alternatives G, H and I
  • the specification unambiguously discloses embodiments corresponding to combinations A, D, G; A, D, H; A, D, I; A, E, G; A, E, H; A, E, I; A,
  • FIG. 1 Rescue of mHTT toxicity by HDGF in PC12 cells and primary neurons.
  • B Cortical neurons transfected with the indicated constructs were fixed at DIV 7+2 and stained for cleaved caspase- 3.
  • FIG. 1 Stereotactic viral delivery of HDGF to the striatum of juvenile mice ameliorates HD phenotypes in the R6/2 line.
  • A Timeline of R6/2 phenotypes and experimental design.
  • B Scheme of bilateral stereotactic AAV injections into the dorsal striatum (left), and overview image of YFP expression in a coronal brain section 3 weeks after injection with AAV8-YFP-P2A- FlagHDGF (right).
  • D Rearing frequency in the open field.
  • F Examples of neuronal mHTT IBs (arrows) detected with EM-48 antibody within the injected area in the striatum of YFP-injected and HDGF- injected R6/2 mice. Neurons were identified with Neurotrace, nuclei were counterstained with DAPI.
  • FIG. 3 Viral delivery of HDGF to the central nervous system of neonatal pups improves motor performance in R6/2 mice.
  • A Timeline of R6/2 phenotypes and experimental design.
  • B Scheme of AAV injections into the lateral ventricle of P0 pups (top), and overview image of a sagittal section from a YFP-P2A-FlagHDGF-injected brain (bottom: Flag and DAPI staining).
  • C Expression of AAV8-YFP-P2A-FlagHDGF in the indicated brain regions at 3 weeks of age. Brain sections were immunostained against Flag and YFP, nuclei were counterstained with DAPI.
  • D Distance traveled in the open field.
  • N 9 WT/YFP mice, 15 WT/HDGF mice, 14 R6/2/YFP mice, 10 R6/2/HDGF mice. *p ⁇ 0.05, ****p ⁇ 0.0001. Scale bars in B, 1mm; C 100pm.
  • FIG. 4 Genetic ablation of HDGF exacerbates motor defects and shortens life span in R6/2 mice.
  • B Rearing frequency in the open field.
  • HDGF wildtype HDGF with nuclear localization
  • HDGF-wt or nucHDGF cytoplasmic HDGF mutant with exclusively cytosolic localization
  • cytHDGF or mHDGF-NES cytoplasmic HDGF mutant with exclusively cytosolic localization
  • NLS nuclear localization signal
  • NES nuclear export signal.
  • the point mutations in the NLS sequences indicated by red lines are: K75N, K78N, R79Q, K80N (in NLS1), and K155N, R156Q, R157Q, K167N, K170N (in NLS2).
  • B Cortical neurons transfected with the indicated constructs were fixed at DIV 7+2 and stained for HDGF. Nuclei were counterstained with DAPI.
  • FIG. 6 Rescue of mHTT toxicity by extracellular HDGF.
  • FIG. 7 Overview of HDGF expression in WT mouse brain.
  • C Images of HDGF fluorescent in situ hybridization combined with HDGF immunostaining in the striatum and cortex of 8-week-old WT (top) and HDGF A (bottom) mice. Nuclei positive for the HDGF protein are marked with dashed lines.
  • FIG. 10 Additional HD phenotype analyses in neonatally injected R6/2 mice.
  • C Body weight.
  • D Kaplan-Meier survival curves.
  • E CAG repeat length of R6/2 mice used for behavior and survival analyses shown in A-D and in Fig. 3D, E.
  • FIG. 11 Genetic ablation of HDGF does not cause differences in grip strength and weight loss in R6/2 mice.
  • B Body weight.
  • N 14 WT::HDGF +/+ mice, 14 WT::HDGF / - mice, 17 R6/2::HDGF /+ mice and 15 R6/2::HDGF / - mice for all analyses in A-C. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • a and D Western blots for phosphorylated (top) and total (middle) ERK1/2. No quantification was performed, as p-ERK was not detectable in HDGF-treated cells.
  • B and E Western blots for phosphorylated (top) and total (middle) Akt. Tubulin was used as a loading control (bottom).
  • FIG. 13 Rescue of a-Syn toxicity by HDGF overexpression.
  • Significant pairwise multiple comparisons are indicated on the graph. *p ⁇ 0.05,
  • Example 1- HDGF reduces mHTT toxicity in PC12 cells and in primary neurons
  • HDGF was found among the proteins that were downregulated in the R6/2 brain (Hosp et al., 2017). It was therefore hypothesized that resupplying HDGF might have beneficial effects in HD models.
  • an inducible stable neuron-like PC12 cell line with pathologically expanded HTT-exon1-74Q fused to GFP (HD-Q74 cells) and a control PC12 cell line with non-pathogenic HTT-exon1-23Q-GFP (HD-Q23 cells) (Wyttenbach et al., 2001) were tested.
  • Example 2- HDGF expression in the brain To address the role of HDGF in vivo, its expression pattern in the wildtype (WT) brain was investigated. Previous studies reported that HDGF is widely expressed during development and in adult tissues, including many regions of the nervous system, where it is found both in neurons and in glial cells (Abouzied et al., 2004; El-Tahir et al., 2006; Zhou et al., 2004). However, expression in different cell types in the brain has not been investigated in detail. Immunostaining experiments in 8-week-old C57BL/6 mice revealed a broad expression of HDGF in the brain, with the expected nuclear localization (Fig. 7A-B). HDGF immunoreactivity was specific, since the signal was absent in HDGF knockout mice (Fig.
  • HDGF staining was combined with various neuronal and glial markers.
  • I Ns ChAT+ cholinergic interneurons
  • GAD+ INs had higher levels of HDGF compared to Neurogranin+ PCs (Fig. 8A-C).
  • SPNs and PCs are the cell types most susceptible to HD, while striatal cholinergic INs and cortical INs are relatively spared.
  • HDGF expression was clearly higher in neurons than in GFAP+ astrocytes, APC+ oligodendrocytes or Iba1+ microglia (Fig.
  • Example 3- HDGF ameliorates motor defects and mHTT aggregation in R6/2 mice
  • HD is an inherited disease
  • gene expansion carriers can be identified, and preventive treatments started at an early age. Therefore, the efficiency of HDGF treatment given to newborn pups was evaluated.
  • YFP-P2A-FlagHDGF or YFP control were overexpressed throughout the brain by AAV injections into the lateral ventricle of P0 pups (Fig. 3A-C).
  • Behavioral assessment at 12 weeks of age revealed a significant recovery of locomotor activity of HDGF- injected R6/2 mice in the open field test (Fig. 3D-E).
  • HDGF-mediated rescue in neonatally injected mice was more pronounced than in mice that received local striatal injections at a juvenile age (Fig. 2C-D).
  • cytHDGF cytosolic version of HDGF
  • mHDGF-NES cytosolic version of HDGF
  • 12 point mutations were introduced into the two nuclear localization sequences of HDGF, resulting in 9 amino acid substitutions, and a nuclear export sequence was added at its C-terminus (Fig. 5A).
  • Immunostaining of transfected primary neurons demonstrated that cytHDGF is excluded from the nucleus and localizes only in the cytoplasm (Fig. 5B).
  • Wildtype HDGF (referred to herein as HDGF, HDGF-wt or nuc-HDGF) and cytHDGF were then co-expressed with mHTT (HTT-exon1-Q72) in primary neurons.
  • mHTT mHTT
  • HTT-exon1-Q25-mCherry and HTT-exon1-Q25-His served as controls, respectively. It was observed that both versions of HDGF increased survival of mHTT-expressing cells, irrespective of which mHTT construct was co-transfected (Fig. 5C and E). Moreover, the frequency of HTT-exon1-Q97-mCherry aggregates was decreased by both HDGF versions (Fig. 5F). For HTT-exon1-Q72-His-transfected cells, the number of neurons with aggregates was high in all conditions, but formation of large (3 1 pm) inclusion bodies was reduced by both nucHDGF and cytHDGF (Fig. 5G). These results indicate that nuclear localization of HDGF is not required for mitigating mHTT toxicity in neurons.
  • Example 6- Extracellular HDGF rescues mHTT toxicity in primary neurons
  • HDGF can be secreted (Nakamura et al., 1994; Oliver and Al-Awqati, 1998; Thirant et al., 2012; Zhou et al., 2004), the potential of extracellular HDGF to modify HD phenotypes in cell culture was investigated.
  • Recombinant nucHDGF or cytHDGF 250 ng/ml was added to dissociated neuronal cultures transfected with pathological (HTT-exon1-Q97-mCherry) or control (HTT-exon1-Q25-mCherry) HTT constructs, and cell viability was measured 2 days later.
  • BDNF brain-derived neurotrophic factor
  • HDGF was used in neurons with a-synuclein (a-Syn) aggregates.
  • a-Syn aggregation is observed in a number of protein misfolding diseases referred to as synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies (DLB) and multiple systems atrophy.
  • synucleinopathies including Parkinson’s disease, dementia with Lewy bodies (DLB) and multiple systems atrophy.
  • DIV 7 Primary mouse neurons were lentivirally transduced on day in vitro 7 (DIV 7) with a-Syn-GFP and YFP-P2A-Flag-HDGF (HDGF-YFP in Fig. 13) or with a-Syn-GFP and YFP as a control.
  • a-Syn in cultured cells does not by itself result in aggregation and toxicity, recombinant a-Syn pre-formed fibrils (“seeds”, 2 pg/ml) were added to the neurons at DIV 7+3 to induce templated seeding of intracellular a-Syn aggregation.
  • HDGF hepatoma- derived growth factor
  • HRP-3 HDGF-related protein-3
  • IGF2 Insulin-like growth factor 2
  • Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals. J Biol Chem 277, 10315- 10322.
  • Adeno-associated virus as a vector for gene therapy. BioDrugs 4, 317-334.
  • TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease. J Neurosci 33, 18712-18727.
  • RNA sequencing the teenage years. Nar Rev Genet 20, 631-656.
  • Hepatoma-derived growth factor binds DNA through the N- terminal PWWP domain.
  • Hepatoma-derived growth factor represses SET and MYND domain containing 1 gene expression through interaction with C-terminal binding protein. J Mol Biol 386, 938-950.
  • Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington's Disease. Cell Physiol Biochem 48, 605-617. Zhou, Z., Yamamoto, Y., Sugai, F., Yoshida, K., Kishima, Y., Sumi, H., Nakamura, H., and Sakoda, S. (2004). Hepatoma-derived growth factor is a neurotrophic factor harbored in the nucleus. J Biol Chem 279, 27320-27326.

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Abstract

La présente invention concerne une protéine ayant une fonction de HDGF (facteur de croissance dérivé de l'hépatome) ou une molécule d'acide nucléique capable d'exprimer une protéine ayant une fonction de HDGF pour une utilisation dans la prévention ou le traitement de maladies neurodégénératives. La présente invention concerne également un procédé de diagnostic d'une maladie neurodégénérative chez un sujet, comprenant I) la détection du niveau d'expression de HDGF dans un échantillon obtenu à partir dudit sujet, et ii) la comparaison dudit niveau d'expression de HDGF avec le niveau d'expression de HDGF dans un échantillon obtenu à partir d'un ou plusieurs sujets sains ou avec un niveau d'expression standard prédéterminé, une régulation à la baisse supérieure à 2 fois étant indicative d'une maladie neurodégénérative chez le sujet.
PCT/EP2022/057062 2021-03-18 2022-03-17 Protéine ayant une fonction de hdgf (facteur de croissance dérivé de l'hépatome) pour une utilisation dans le traitement et la prévention de maladies neurodégénératives Ceased WO2022195042A1 (fr)

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