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WO2025176642A1 - Procédé de préparation d'une composition de vésicule extracellulaire, composition de vésicule extracellulaire et utilisation associée - Google Patents

Procédé de préparation d'une composition de vésicule extracellulaire, composition de vésicule extracellulaire et utilisation associée

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Publication number
WO2025176642A1
WO2025176642A1 PCT/EP2025/054295 EP2025054295W WO2025176642A1 WO 2025176642 A1 WO2025176642 A1 WO 2025176642A1 EP 2025054295 W EP2025054295 W EP 2025054295W WO 2025176642 A1 WO2025176642 A1 WO 2025176642A1
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WO
WIPO (PCT)
Prior art keywords
cells
stem cells
composition
medium
mir
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Pending
Application number
PCT/EP2025/054295
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English (en)
Inventor
Didier Serteyn
Justine CEUSTERS
Julien DUYSENS
Hélène GRAIDE
Charlotte Sandersen
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Revatis Sa
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Revatis Sa
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Publication of WO2025176642A1 publication Critical patent/WO2025176642A1/fr
Pending legal-status Critical Current
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • C12N5/0668—Mesenchymal stem cells from other natural sources
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/65—MicroRNA
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/90—Polysaccharides
    • C12N2501/91—Heparin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C12N2502/1352—Mesenchymal stem cells
    • C12N2502/1388—Mesenchymal stem cells from other natural sources
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2509/00—Methods for the dissociation of cells, e.g. specific use of enzymes

Definitions

  • EVs are sometimes categorized by their size. They are much smaller than cells and show a dimension of approx. 30 to 2000 nm. Exosomes are considered a subclass of EVs and generally show a dimension below 150 nm. Other subclasses are ectosomes or microvesicles (100 to 1000 nm) and apoptotic bodies (500 to 2000 nm).
  • EVs which were considered cell debris actually serve as mediators for cell-to-cell communication.
  • nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of the cells of origin or producer cells, EVs and more specifically exosomes can be used as cell-free therapeutics.
  • mesenchymal stem cell-derived exosomes have gained great attention due to their immunomodulatory and regenerative functions.
  • MSC-derived EVs can transfer miRNAs to target cells, modulating various physiological processes including cell proliferation, differentiation, and immune responses. For instance, studies have demonstrated that MSC-EV miRNAs contribute to osteoblastic differentiation, angiogenesis, and the modulation of inflammatory responses. The therapeutic potential of MSC-derived miRNAs extends to various pathological conditions. In the context of musculoskeletal disorders, EV-miRNAs have been found to exhibit teno- and chondro-protective properties, as well as the ability to induce M2 macrophage polarization and promote regulatory T cells. Furthermore, MSC-EV miRNAs have shown promise in suppressing fibrosis by preventing fibroblast differentiation into myofibroblasts. There, however, still is a need for efficient production methods that generate EVs of consistent quality.
  • Step (iii) advantageously comprises subjecting the cell-containing isotonic electrolyte solution to a gentle mechanical stimulation designed to favor secretion of EVs.
  • gentle mechanical stimulation may advantageously consist in a gentle centrifugation.
  • “gentle centrifugation” is understood to mean a centrifugation at 100 - 400 g, preferably at 150 - 350 g, more preferably at 200 - 300 g during a time period of 1 - 30 min, preferably 5 - 20 min, or 5 - 15 min, more preferably around 10 min.
  • gentle centrifugation has shown to be a preferred method for extraction of the desirable EVs per the invention, other gentle methods may be used, such as a combination of a mechanical stimulation by ultrasound or agitation with filtration.
  • compositions also comprise certain desirable miRNAs of interest, such as EV-derivable miRNAs, which are believed to sustain the pharmaceutical effect of said compositions.
  • compositions have been shown in regenerative and healing processes. They promote tissue repair across various models, including liver fibrosis, autoimmune keratitis or uveoretinitis and myocardial infarction. They have also demonstrated to promote angiogenesis and accelerate wound healing. They further sustain anti-infective effects in relevant treatments.
  • Suitable galenic forms may be designed for topical or systemic application.
  • Pharmaceutical compositions containing the invention composition possibly together with other pharmaceutical actives or pharmaceutically acceptable carrier and/or extender may obviously be adapted for appropriate administration to the patient in need, in accordance to known techniques. Examples are subcutaneous or intravenous administration formulae.
  • Figure 5 shows the effect of exosome-free supernatant and resuspended exosomes as obtained after ultracentrifugation, in a SIEFED test.
  • stem cell refers generally to an unspecialised or relatively less specialised and proliferation-competent cell, which is capable of self-renewal, i.e., can proliferate without differentiation, and which or the progeny of which can give rise to at least one relatively more specialised cell type.
  • the term encompasses stem cells capable of substantially unlimited selfrenewal, i.e., wherein the progeny of a stem cell or at least part thereof substantially retains the unspecialised or relatively less specialised phenotype, the differentiation potential, and the proliferation capacity of the mother stem cell, as well as stem cells which display limited selfrenewal, i.e., wherein the capacity of the progeny or part thereof for further proliferation and/or differentiation is demonstrably reduced compared to the mother cell.
  • a stem cell may give rise to descendants that can differentiate along one or more lineages to produce increasingly relatively more specialised cells, wherein such descendants and/or increasingly relatively more specialised cells may themselves be stem cells as defined herein, or even to produce terminally differentiated cells, i.e., fully specialised cells, which may be post-mitotic.
  • mesenchymal stem cell refers to a mammalian adult, mesoderm-derived stem cell that is capable of generating cells of mesenchymal lineages, typically cells of two, preferably of three or more mesenchymal lineages, e.g., osteocytic (bone), chondrocytic (cartilage), myocytic (muscle), tendonocytic (tendon), fibroblastic (connective tissue), adipocytic (fat) and stromogenic (marrow stroma) lineage.
  • mesenchymal lineages typically cells of two, preferably of three or more mesenchymal lineages, e.g., osteocytic (bone), chondrocytic (cartilage), myocytic (muscle), tendonocytic (tendon), fibroblastic (connective tissue), adipocytic (fat) and stromogenic (marrow stroma) lineage.
  • isolated with reference to a particular component denotes separating that component from at least one other component of a composition from which the former component is thereby “isolated”.
  • isolated used in relation to any cell, group of cells or a cell population also implies that such cell, group of cells or cell population does not form part of an animal body.
  • the ISCT determined precisely the qualities cells must possess to be defined as mesenchymal stem cells (MSCs) as follows: the cells must be plastic-adherent, positive for the markers CD73, CD90 and CD105, negative for the markers CD14 (or CD11 b), CD34, CD45, CD79a (or CD19) and MHC-II, and must exhibit the ability to differentiate into cells of mesodermal origin such as osteoblasts, chondroblasts and adipocytes (Dominici et al., 2006). The use of other MSC markers such as CD29 or CD44 was also reported (Pittenger et al., 1999). The ISCT criteria were extended to the invention herein.
  • MSCs mesenchymal stem cells
  • the mammalian MSC cells hence are defined in that they express or co-express (i.e., are positive for) at least the mesenchymal marker CD105, and preferably also one or more of the following markers: CD44 and CD90.
  • the mammalian MSC cells are also defined in that they express or co-express (i.e., are positive for) one or more of the following microRNAs: miR-128, miR-133B, miR-218 or miR-802.
  • the mammalian MSC cells are also defined in that they do not express miR-656.
  • co-express intends to cover the meaning “comprising coexpression of' such that the cells can express other markers or microRNAs in addition to the particular recited markers or microRNAs characterising the cells.
  • cell-specific markers can be detected using any suitable immunological technique known in the art, such as immuno-cytochemistry or affinity adsorption, Western blot analysis, FACS, ELISA, etc., or by any suitable biochemical assay of enzyme activity, or by any suitable technique of measuring the quantity of the marker mRNA, e.g., Northern blot, semi-quantitative or quantitative RT-PCR, etc.
  • immunological technique such as immuno-cytochemistry or affinity adsorption, Western blot analysis, FACS, ELISA, etc.
  • biochemical assay of enzyme activity or by any suitable technique of measuring the quantity of the marker mRNA, e.g., Northern blot, semi-quantitative or quantitative RT-PCR, etc.
  • microRNAs may be referred to by different names, or synonyms.
  • cell population generally refers to a grouping of cells.
  • a cell population may consist of or may comprise at least a fraction of cells of a common type, or having characteristics in common. Such characteristics may include, without limitation, morphological characteristics, potential for differentiation (e.g., pluripotent, multipotent, unipotent, etc.; e.g., if multipotent or unipotent, ability to differentiate towards specific cell types), or the presence and/or level of one, two, three or more cell-associated markers, e.g., surface antigens. Such characteristics may thus define a cell population or a fraction thereof.
  • a cell population is mesenchymal stem cell population, more preferably a substantially homogenous population of mesenchymal stem cells.
  • mammal refers to all mammals, including, but not limited to, domestic and farm animals, zoo animals, sport animals, pet animals, companion animals and experimental animals, such as, for example, mice, rats, hamsters, rabbits, dogs, cats, guinea pigs, cattle, cows, sheep, horses, pigs and primates, e.g., monkeys and apes, but also humans.
  • Preferred mammals are horses, dogs, or cats.
  • Serum is also believed to protect the cells against physical chocs as it is a viscous liquid. Serum is further known to control the osmotic balance between the cells and the external medium and to control chemical parameters like protease inhibition. Other cell culture methods are known; reference is made in this respect to WO2021/165451 for instance.
  • Nattokinase is an enzyme extracted from natto food which is fermented in the presence of Bacillus subtilis var. natto which in turn produces the enzyme.
  • the exact chemical structure may slightly vary depending on bacterial line and/or fermentation conditions.
  • Trypsin is a serine-based enzyme generated in mammalian pancreas and which hydrolyses peptide bonds, more specifically of adhesion proteins which bond cell walls to a synthetic support. It is commonly used in cell culture for dissociation of grown cells. The precise chemical structure may vary depending on the source. Moreover, serine-based derivatives showing trypsin-like enzymatic activity have been prepared that are more suited for selected applications. Synthetic variants showing trypsin-like enzymatic activity are also available on the market. Unless specified otherwise, the term “trypsin” covers natural variants, derivatives and synthetic variants.
  • equivalent concentration of x cells/ml used in connection with the supernatant is understood to mean the concentration of EVs and other components in the supernatant resulting from x cells/ml used as starting cell suspension for secretion of EVs.
  • the stem cells have been grown in DMEM-Ham’s F12 (Dulbecco’s modified Eagle Medium) base medium supplemented with 10% by volume equine platelet rich plasma and 1.4 lU/ml Heparin. Said culture medium is xenofree. Preferably, the stem cells are grown to near 80% confluence.
  • the stem cells obtained may be dissociated or detached from their support and may also be dissociated from one another.
  • the cultured stem cells are washed with a dissociation composition. Trypsin is well known to that effect.
  • a particularly gentle synthetic trypsin alternative more specifically TrypLe (sourced from Gibco) has been used to cleave relevant bonding of the stem cells to one another and to their support. The reactions are stopped by addition of PBS buffer.
  • the obtained mixture may then be subjected to a gentle or mild centrifugation.
  • a centrifugation at approx. 300 g can be applied during approx.10 minutes.
  • the supernatant is to be discarded and the residue comprising the stem cells is resuspended in isotonic electrolyte solution, such as Ringer lactate.
  • the cells grown in step (i) may be directly rinsed with isotonic electrolyte solution, such as Ringer lactate.
  • the obtained mixture of cells in electrolyte solution is subjected to mild centrifugation, such as a centrifugation at approx. 300 g during approx. 10 min, which stimulates the secretion of EVs from the cells into the medium.
  • the residue or deposit or pellet, that is the cells is discarded and the supernatant comprising the EVs is retained as product of interest. If so required, it may be subjected to yet another centrifugation at approx. 2000 g for approx. 10 min in order to eliminate undesirable components and cell debris.
  • the discarded cells may be reused in cell culture, or even returned to the cell culture step (i), or subjected to cryopreservation.
  • the final composition comprises EVs in a simple buffer solution and can be used directly as such in or as a pharmaceutical composition.
  • the invention process is simple and comprises steps that are well known per se and easy to operate.
  • the processing conditions are mild and as a result, high quality stable EVs are obtained.
  • the invention process does not comprise any process step that is rather aggressive towards EVs. More specifically, the invention process does not include any ultracentrifugation step.
  • the EV containing Ringer lactate solution can advantageously be stored at -20 °C to -80 °C for extended periods of time and that the EVs collected remain stable over extended periods of time.
  • the product obtained by the invention process thus shows a significant advantage.
  • the invention process generates a composition comprising EVs, including exosomes, production cell-originating immunomodulatory proteins and other cell-originating proteins and/or peptides or miRNAs in suspension in isotonic solution; here Ringer lactate.
  • the product obtained is of interest in pharmaceutical treatments.
  • the composition resulting from the invention process shows unexpected pharmaceutical effects and may be used for treating one or more of the disorders, such as Systemic Inflammation Response Syndrome (SIRS); Acute Respiratory Distress Syndrome (ARDS), acute or degenerative conditions within the systems composing the mammalian body, such as the circulatory system, the digestive system, the immune system, the integumentary system, the musculoskeletal system, the nervous system, the reproductive system, the respiratory system and the urinary system. More specifically the invention composition may be used to treat one or more disorders of several organs as liver, lung, heart, uterus, brain, eye, skin, bone, tendon and cartilage, in mammalian subjects.
  • SIRS Systemic Inflammation Response Syndrome
  • ARDS Acute Respiratory Distress Syndrome
  • the invention composition may be used to treat one or more disorders of several organs as liver, lung, heart, uterus, brain, eye, skin, bone, tendon and cartilage, in mammalian subjects.
  • Example 1 Material and methods - Cell culture and medium composition
  • microbiopsy specimen was carefully dissected (trying to keep as much as possible only muscular tissue, hence eliminating fibrous tissue parts).
  • the microbiopsy specimens then were cut in small pieces (size of the tip of the scalpel blade). Culture preparation was performed by use of sterile equipment, under a streamline flow hood. Each piece was placed individually into the 16 central wells of a 24- mutliwell dish, each well comprising 400pl of culture medium.
  • the culture medium consisted in a mixture of 500mL DMEM-F12 (Lonza) supplemented with 10% of equine platelet rich plasma (PRP) and Heparin at a final concentration of 1 ,44IU/mL into the whole medium.
  • PRP is obtained thanks to a GMP plasmapheresis COM. tec from Fresenius Kabi. Pooches of 100 to 800 mL are generated and stored in 50 ml Falcon. The multi-well dish was then incubated at 37°C under controlled atmosphere (5% CO2) for several days. A migration of cells occurred.
  • mesenchymal stem cells are detached from the flask with TrypLe and after 5 minutes, PBS (phosphate buffer saline) is used to stop the TrypLe activity.
  • PBS phosphate buffer saline
  • a first centrifugation at 300g for 10 min is performed to collect cells in the pellet. Then, supernatant is discarded and cells are resuspended with Ringer Lactate to obtain a final concentration of 100,000 cells/mL.
  • a second centrifugation at 300g for 10min is performed in order to obtain the secretome of these cells. After that, cells (in the pellet) are cryopreserved and the supernatant is collected.
  • Example 3 Evaluation of EV composition on myeloperoxidase (MPO) activity
  • FIG. 2 is a schematic representation of the experiment. It is based on a plaque coated with antibodies against equine MPO. A defined equivalent concentration of 100,000 cells/mL of the EV containing lactate solution was added into the wells and a known concentration of MPO was added. A 2h-incubation at 37°C was performed before revealing the fluorescence.
  • Example 4 Evaluation of EV composition on Lymphocyte proliferation
  • PBMC peripheral blood mononuclear cells
  • RPMI 1640 supplemented with 10% FBS, 5 mM of L-Glutamine, 0.1 mM of 2-Mercaptoethanol (and optionally Amphotericin B and Penicillin/streptomycin mixture).
  • PBMC peripheral blood mononuclear cells
  • results were obtained by visual assessment of the proliferation of the stimulated PBMC with a manual count of the cells in each experimental condition.
  • the difference in cell counts between the stimulated PBMC in contact or not with the invention and the unstimulated ones was then translated in percentage of inhibition of the lymphocyte proliferation.
  • the invention composition comprising EVs in Ringer lactate was prior-incubated with magnetic balls containing antibodies against CD9, CD63 and CD81 to isolate EVs.
  • the specific EVs, fixed onto these magnetic balls, were then incubated with a mix of different secondary antibodies against 39 different CD proteins (detection cocktail).
  • the emitted fluorescence is a measure of the quantity of EVs expressing specific CD proteins amongst the 39 of the detection cocktail.
  • the EVs contained in the composition expressed CD9, CD63, CD81 , CD29, CD49 e , CD105, and CD44 in different proportion depending of their origin, human or equine.
  • Nanosight device To determine the amount and quality of EVs (and among them exosomes), an analysis with a Nanosight device was performed. This tool measures nanoscale particles by laser scattering in the range of 10 nm -1000 nm. Particle-by-particle analysis assures high resolution size and concentration data with visual confirmation.
  • the equine EVs of interest contained in the composition have a mean (arithmetic) size of 207,03 ⁇ 4,27nm with a high peak at 200nm and a mean concentration of 4,42x10 8 ⁇ 2,02x10 7 particles/mL.
  • the mean size is 234,27 ⁇ 6,97nm with a mean concentration of 2,57x10 8 ⁇ 3,40x10 6 particles/mL.
  • Example 6 Therapeutical application of the invention composition against IMMK
  • IMMK International Mediated Keratitis
  • IMMK is a nonulcerative keratitis of idiopathic origin commonly diagnosed in veterinary ophthalmology. IMMK is characterized by varying degrees of conjunctival hyperaemia, cellular infiltration, corneal vascularization, corneal oedema, calcific degeneration, and fibrosis. IMMK usually necessitates long-term medical treatment.
  • Existing therapeutic approaches focus on reducing the inflammatory reaction and typically encompass a combination of local corticosteroid, non-steroidal anti-inflammatory drug, or cyclosporine administration, alongside systemic administration of steroidal or non-steroidal antiinflammatory drugs. Therapy can be challenging, as the disease often becomes increasingly refractory to medical treatment and prone to recurrence over time. In addition, prolonged use of steroidal anti-inflammatory treatment can lead to corneal degeneration.
  • the invention composition consisted in a Ringer lactate solution comprising EVs secreted from equine MSCs (obtained according to W02015/091210) and prepared in accordance with the invention process at a concentration of 3-5 x 10 9 EVs/ml.
  • the severity of the disease was assessed by a scoring system (see Table 2).
  • the invention treatment consisted of the administration of the invention composition at a rate of 2 drops 3 times a day for 30 days. 5 cases are reported in Table 3. None of the horses experienced ocular discomfort. Conjunctival hyperaemia improved in all cases. All cases exhibited a reduction in cellular infiltration after the first week. All eyes responded positively to the therapy, with a significant reduction of the total lesion score.
  • figure 3 shows two cases (left and right pictures) before and after (top and lower pictures) the invention treatment.
  • the positive effects observed by the administration of the invention treatment is explained by the potent immunomodulatory effects of extracellular vesicles.
  • these findings provide valuable insights into the potential benefits of the invention composition for managing IMMK.
  • EX1 first attack in November 2022. Received cyclosporine-dexamethasone during 2 months. Good response. Treatment stopped in May 2023. Recurrence in September 2023.
  • EX2 Affected during 2 years. Received terramycin.
  • EX5 Doiagnosed in 2009. Frequent recurrences in winter, controlled in summer. In case of crisis: dexamethasone and finadyne, then cyclosporine. Keratitis remained under control until January 2023 when a new attack was detected and treatment with dexamethasone, diclofenac, Trafloxal and tacrolimus was initiated. Recurrence on gradual cessation of treatment.

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Abstract

La présente invention concerne un nouveau procédé de préparation d'une composition comprenant une vésicule extracellulaire (VE), le procédé comportant les étapes suivantes : (i) culture de cellules souches dans un milieu de culture ; dissociation éventuelle des cellules souches obtenues à l'étape (i) de leur support et séparation éventuelle des cellules souches du milieu utilisé à l'étape (i) ; (ii) rinçage des cellules souches obtenues dans une solution d'électrolyte isotonique ; (iii) soumission de la solution d'électrolyte isotonique contenant les cellules à une légère stimulation mécanique et séparation des cellules du milieu et conservation du milieu, les cellules séparées étant rejetées ; et (iv) séparation éventuelle des composants indésirables restants, des cellules et des débris cellulaires du milieu d'intérêt conservé à l'étape (iii) Les cellules rejetées peuvent être utilisées dans d'autres cycles de culture et/ou pour d'autres applications. La composition contenant l'EV de l'invention comporte en outre des protéines immunomodulatrices d'origine cellulaire et des miARN et peut être utilisée dans le traitement de troubles sélectionnés parmi le syndrome de réponse à l'inflammation systémique (SIRS), le syndrome de détresse respiratoire aiguë (SDRA), les affections aiguës ou dégénératives de plusieurs organes tels que le foie, les poumons, le cœur, l'utérus, le cerveau, les yeux, la peau, les os, les tendons et le cartilage, sur des sujets mammifères.
PCT/EP2025/054295 2024-02-19 2025-02-18 Procédé de préparation d'une composition de vésicule extracellulaire, composition de vésicule extracellulaire et utilisation associée Pending WO2025176642A1 (fr)

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WO2020136362A1 (fr) 2018-12-28 2020-07-02 Centre National De La Recherche Scientifique Système fluidique de production de vésicules extracellulaires et procédé associé
WO2021165451A1 (fr) 2020-02-21 2021-08-26 Revatis Sa Culture de cellules souches
WO2022008652A1 (fr) 2020-07-09 2022-01-13 Exo Biologics Sa Vésicules extracellulaires (ve) dérivés de cellules stromales mésenchymateuses et procédé d'obtention de ces ve.
WO2022204955A1 (fr) 2021-03-30 2022-10-06 Shenzhen ChuangSheng XinKe Biotechnology Co., Ltd. Procédé de préparation d'exosomes à partir d'ipsc et de ses dérivés pour toute utilisation clinique de ces derniers
EP4144836A1 (fr) 2020-04-28 2023-03-08 Konkuk University Industrial Cooperation Corp. Procédé de production de vésicules extracellulaires à partir de cellules souches mises en culture en trois dimensions
WO2023056272A1 (fr) 2021-09-29 2023-04-06 Capsugel Italy S.R.L. Procédés de traitement et d'analyse de vésicules extracellulaires
US11801268B2 (en) 2016-03-14 2023-10-31 Capricor, Inc. Methods of treating ocular inflammation and chemical injuries of the eye with extracellular vesicles

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WO2015091210A1 (fr) 2013-12-19 2015-06-25 Universite De Liege Cellules souches dérivées de muscles d'origine mammifère
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