WO2023166301A1 - Thérapie génique glis3-manf pour la prévention ou le traitement du diabète - Google Patents

Thérapie génique glis3-manf pour la prévention ou le traitement du diabète Download PDF

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WO2023166301A1
WO2023166301A1 PCT/GB2023/050491 GB2023050491W WO2023166301A1 WO 2023166301 A1 WO2023166301 A1 WO 2023166301A1 GB 2023050491 W GB2023050491 W GB 2023050491W WO 2023166301 A1 WO2023166301 A1 WO 2023166301A1
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manf
tissue
glis3
organ
pathway
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James Dooley
Adrian LISTON
Kailash Singh
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Katholieke Universiteit Leuven
Vlaams Instituut voor Biotechnologie VIB
Babraham Institute
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Katholieke Universiteit Leuven
Vlaams Instituut voor Biotechnologie VIB
Babraham Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination

Definitions

  • the invention relates to a pharmaceutical composition for use in preventing and/or treating diabetes, said composition comprising a modulator of the Glis3-Manf pathway and a targeting moiety specific for a tissue or organ of a subject, such as the pancreas. Also provided are viral vectors and methods for preventing and/or treating diabetes.
  • Diabetes is a disease of dysfunctional glucose regulation.
  • the predominant forms of diabetes are type 1 diabetes (T1 D) and type 2 diabetes (T2D), although there are a diverse set of additional forms, which include aspects of one or both diseases.
  • T1 D disease is initiated and caused by inheritance of an adaptive immune system that is predisposed to responding beta-cell antigens, most notably to insulin itself (Roizen et al. (2015) Curr Diab Rep 15, 102).
  • T1 D disease is initiated and caused by inheritance of an adaptive immune system that is predisposed to responding beta-cell antigens, most notably to insulin itself (Roizen et al. (2015) Curr Diab Rep 15, 102).
  • autoimmunity being effectively established by three years of age in over 80% of cases, most patients are diagnosed many years, or even decades, after establishment of persistent anti-islet autoimmunity (Bonifacio et al. (2017) Diabetologia 60, 35-38.
  • T2D is not an autoimmune disease.
  • normally insulin-responsive cells such as hepatocytes
  • T2D is ill-defined (Heianza, Y. et al. (2012) Diabet Med 29, e279- 285), with pancreatic beta-cells initially able to compensate for insulin resistance by increasing the amount and duration of insulin secretion.
  • pancreatic beta-cells initially able to compensate for insulin resistance by increasing the amount and duration of insulin secretion.
  • Many patients remain in a grey area of diagnosis at this stage, where diet modification and anti-diabetogenic drugs are sufficient to avoid the prolonged hyper-glycemia that is the pathological outcome of untreated T2D.
  • the beta-cell fragility model can be defined as one where variation in the intrinsic fragility or robustness of beta-cells contributes to the development of diabetes. Just as susceptibility to autoimmunity and insulin resistance varies across individuals, due to genetic and environmental influences, beta-cells vary across individuals in their ability to survive autoimmune or metabolic insults (Liston et al. (2017), supra). The presence of “fragile” beta-cells in an individual would sensitize for diabetes, either T1 D, for individuals with autoimmune susceptibility, or T2D, for individuals with metabolic stress. By contrast, individuals with “robust” beta-cells would be more likely to remain at a pre- clinical stage with delayed diabetes development. Under this model, increasing the robustness of beta-cells would be an effective therapeutic strategy for individuals at high risk for either T1 D or T2D, or to prevent further progression of T2D.
  • a therapy for diabetes such as a targeted therapy which may be used to treat/relieve diabetes and related disorders.
  • a pharmaceutical composition comprising a modulator of the Glis3-Manf pathway and a targeting moiety specific for a tissue or organ of a subject for use in preventing and/or treating diabetes.
  • an adeno-associated virus (AAV) vector which encodes:
  • a pharmaceutical composition comprising a modulator of the Glis3-Manf pathway and a targeting moiety specific for a tissue or organ of a subject for use in preventing and/or treating diabetes.
  • references herein to “modulator of the Glis3-Manf pathway” refer to any component which modulates (i.e. inhibits, agonises, antagonises etc) the Glis3-Manf pathway.
  • the modulator of the Glis3-Manf pathway is G I is3.
  • Giis3 GUS Family Zinc Finger 3
  • This protein functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. Mutations in this gene have been associated with neonatal diabetes and congenital hypothyroidism (NDH). Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only two have been determined.
  • the modulator of the Glis3-Manf pathway is Manf.
  • Mesencephalic astrocyte-derived neurotrophic factor (Manf) is a small protein with a molecular mass of 18 kDa. It contains an amino-terminal signal peptide that directs it to the endoplasmic reticulum (ER) and, when cleaved, results in a mature protein that can be secreted.
  • ER endoplasmic reticulum
  • tissue or organ refers to a discrete location in the subject such as in a particular tissue or organ. It will be appreciated that such terms do not relate to wherein an effect is produced systemically or outside of the tissue or organ of interest, or wherein a cell type or cell population not located in the tissue or organ of interest is affected.
  • Tissues or organs as defined herein comprise a discrete location of the body or of an organism.
  • the tissue or organ may comprise a compartment of the body.
  • the tissue or organ is the pancreas.
  • the tissue or organ is the pancreatic islets.
  • the tissue or organ is the beta cells of the pancreatic islets.
  • T1 D The primary animal model of T1 D is the non-obese diabetic (NOD) mouse, which hosts a large set of genetic polymorphisms increasing susceptibility to anti-islet autoimmunity (Wicker et al. (2005) J Autoimmun 25 Suppl, 29-33).
  • NOD non-obese diabetic
  • NSTE Nagoya-Shibata-Yasuda mice
  • the laboratory of the present inventors performed a molecular dissection of NOD genetic control over beta cell viability and found strong evidence that the shared component of diabetes susceptibility may be dependent on beta-cell fragility.
  • NOD mice possess variants in Glis3 that have beta-cell-intrinsic functions, rendering the beta-cells highly susceptible to apoptosis (Dooley et al. (2016), supra).
  • beta-cell stressors that mimic the compensatory insulin overproduction observed in T2D, this beta-cell fragility is sufficient to tip the mice into overt diabetes, while the same stressors remain sub-clinical in mice with robust beta-cells (Dooley et al. (2016), supra).
  • the present inventors drove expression of Manf in the beta-cells of NOD mice using the insulin promoter.
  • gene delivery of Manf substantially lowered the rate of diabetes development in treated mice, proof-of-principle that correcting beta cell fragility can avert clinical diabetes progression (see Example 1 and Figure 1).
  • the method of preventing and/or treating diabetes comprises administration of the modulator of the Glis3-Manf pathway, such as tissue- or organ-specific expression of said modulator of the Glis3-Manf pathway in said tissue or organ of the subject.
  • tissue- or organ-specific expression of the modulator of the Glis3-Manf pathway is driven by a tissue- or organ-specific promoter.
  • tissue- or organ-specific promoter is a pancreas specific promoter.
  • the pancreas specific promoter is an insulin promoter.
  • administration of the modulator of the Glis3-Manf pathway or tissue- or organ-specific expression of the modulator of the Glis3-Manf pathway in said tissue or organ comprises an exogenous encoding sequence of the modulator of the Glis3-Manf pathway.
  • AAV Adeno-Associated Virus
  • the targeting moiety specific for the tissue or organ of the subject is a virus or viral vector as defined herein.
  • said virus or viral vector specifically targets or infects the tissue or organ of interest or specifically targets or infects cells of the tissue or organ of interest (i.e. the pancreas).
  • said targeting moiety specific for the tissue or organ of interest which is a virus or viral vector does not target or infect cells in other tissues or organs other than the tissue or organ of interest, or target or infect cells which make up a tissue or organ other than the tissue or organ of interest.
  • the viral vector is an adeno-associated virus (AAV) vector which specifically targets or infects the tissue or organ.
  • the adeno- associated virus (AAV) vector is an AAV8 adeno-associated virus (AAV) vector.
  • an adeno-associated virus (AAV) vector which encodes:
  • the modulator of the Glis3-Manf pathway is as defined herein and includes for example Glis-3 or Manf, such as Manf.
  • tissue or organ specific promoter is as defined herein and includes a pancreas specific promoter, such as an insulin promoter.
  • the pharmaceutical composition in addition to the modulator of the Glis3-Manf pathway and the tissue or organ specific virus or viral vector as defined herein, further comprises one or more pharmaceutically acceptable excipients.
  • the present pharmaceutical compositions will be utilised with pharmacologically appropriate excipients or carriers.
  • these excipients or carriers include aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and/or buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride and lactated Ringer's.
  • Suitable physiologically-acceptable adjuvants if necessary to keep a composition comprising the targeting moiety specific for a tissue or organ as defined herein in a discrete location (e.g.
  • Intravenous vehicles include fluid and nutrient replenishers and electrolyte replenishers, such as those based on Ringer's dextrose. Preservatives and other additives, such as antimicrobials, antioxidants, chelating agents and inert gases, may also be present (Mack (1982) Remington's Pharmaceutical Sciences, 16 th Edition).
  • a method of preventing and/or treating diabetes in a subject in need thereof comprising administering to the subject the pharmaceutical composition or the vector as defined herein.
  • Diabetes mellitus commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Examples of diabetes include Type 1 diabetes (T1 D), Type 2 diabetes (T2D) and gestational diabetes. In one embodiment, said diabetes is Type 1 diabetes (T1 D). In an alternative embodiment, said diabetes is Type 2 diabetes (T2D).
  • T1 D Type 1 diabetes
  • T2D Type 2 diabetes
  • references herein to diabetes also include diabetic related disorders.
  • diabetic related disorders include celiac disease, thyroid disease, polycystic ovary syndrome, diabetes insipidus, necrobiosis lipoidica diabeticorum, mastopathy, muscular conditions including limited joint mobility, frozen shoulder, Dupuytren’s contracture, trigger finger, carpal tunnel syndrome, dental problems, haemochromatosis, insulin resistance and severe insulin resistance, diabetic retinopathy, and pancreatitis.
  • Example 1 Gene delivery of Manf to beta-cells of the pancreatic islets averts type 1 diabetes development
  • NOD mice were inbred and housed under semibarrier conditions in an animal facility, and fed a standard chow diet. Ten-week-old female NOD mice were used. Allocation to treatment group was made randomly at weaning, at the cage level. All experiments were performed in accordance with the University of Leuven Animal Ethics Committee guidelines. Sample sizes for mouse experiments were chosen in conjunction with the Animal Ethics Committee to allow for robust sensitivity without excessive use.
  • mice were kept until 30 weeks of age and tested twice per week for glucose dysregulation by blood glucose and urine assessment with Diastix Reagent Strips (Bayer). Mice were diagnosed as diabetic when blood glucose went over 250mg/dL (13.9 mmol/L) for two consecutive readings, coupled with a positive urine glucose test. Glucose testing was performed on a blinded basis, with mice being coded by number until experimental end.
  • AAV production was performed by VectorBuilder (Neu-lsenburg, Germany), using the classical tri-transfection method, with subsequent vector titration performed using a qPCR- based methodology (Fripont et al. (2019) J Vis Exp 29, 143; Rincon et al. (2016) Gene Ther 25, 83-92).
  • the mouse Manf coding sequence (accession number NM_029103.4) was cloned into a single stranded AAV2-derived expression cassette, containing the 705bp rat Insulin 2 promoter, woodchuck hepatitis post-transcriptional regulatory element (WPRE) and bovine growth hormone polyadenylation (bGH polyA) sequence.
  • Control vectors (AAV8./ns-GFP) were prepared by swapping the Manf coding sequence for that encoding enhanced green fluorescent protein (EGFP, Vector Biolabs). Vector (100 pl total volume) was administered to mice via the interperitoneal route at 1x10 10 vector genomes/dose.
  • the present inventors developed a gene delivery-based therapeutic system to deliver Manf to the islets in vivo.
  • An AAV gene delivery system was used to drive the endogenous production of Manf in the islets, using the AAV8 capsid and the rat insulin promoter (AAV8./ns-Manf).
  • Pre-diabetic NOD mice at 10 weeks of age, were treated with either AAV8./ns-Manf or the control AAV8./ns-GFP vector, and monitored for diabetes development (Figure 1).
  • These results suggest that gene delivery of Manf to the betacells is capable of increasing islet robustness, providing a potential pathway to therapeutic use in diabetes patients.
  • the ability of AAV8./ns-Manf treatment to drive expression of Manf has been demonstrated in Singh etal. (2022) Biomolecules, 12, 1493 (doi: htlps://dpLprg/10.3390/ biom12101493) in which a substantial upregulation of Manf, specifically within the beta-cell compartment was observed, thus indicating that the AAV8./ns-Manf vector is capable of efficient beta-cell specific gene delivery of Manf.
  • GLIS3 is also a key anti-apoptotic mediator in humans.
  • GLIS3 expression is accompanied by a reduction in GLIS3 expression (Hall et al. (2014) BMC Med 12, 103; Cnop et al. (2014) Diabetes 63, 1978-1993), and beta-cell apoptosis (in response to palmitate or inflammatory cytokines) is compounded by GLIS3 knockdown (Nogueira et al. (2013), supra).
  • GLIS3 polymorphism being linked to susceptibility to both T1 D and T2D (Barrett et al. (2009) Nature genetics 41 , 703-707; Dupuis etal. (2010) Nature genetics 42, 105-116; Li etal. (2013) Diabetes 62, 291-298; Cho et al.
  • Manf is a critical survival factor for pancreatic beta cells, with Manf-deficient mice developing spontaneous diabetes due to beta cell apoptosis (Lindahl et al. (2014), supra). Manf demonstrates one of the largest increases in expression following induction of the unfolded protein stress response (Dooley et al. (2016), supra), suggesting it is a programmed stressresponse pathway that enables continued survival. The same process is conserved in humans, with the addition of recombinant MANF protecting human pancreatic beta-cells from stress-induced apoptosis (Hakonen et al. (2016) Diabetologia 61 , 2202-2214). Evidence suggests that effective MANF upregulation during stress requires Glis3 expression.
  • AAV-based gene delivery system raises the potential for translation to the human context. While viral vector-based therapeutics have had delayed uptake, improved safety profiles of modern vectors are driving a renaissance in gene delivery and gene therapy clinical trials, with nearly half of the currently open clinical trials based on AAVs. An improved robustness of beta-cells during cellular stress could be clinically beneficial in three different clinical contexts.
  • the system could be used to protect against T1 D. Improved genetic and serology-based prediction may allow the identification of children pre-disposed to T1 D, for treatment prior to clinical onset. Alternatively, recent-onset T1 D patients may be treated.
  • the “honeymoon phase” that recent-onset T1 D patients only enter following exogenous insulin treatment suggests that both remaining betacell mass is present, and also that the retained cells are operating in a sub-optimal manner due to excessive metabolic stress from insulin production. Increased robustness of these islets may prolong the honeymoon phase and reduce dependence on exogenous insulin.
  • the system could be used to improve islet transplantation. Transplanted islets have poor survival rates, and the transplantation process could be used as a window for exposure to AAV-based MANF buffering. Highly robust transplanted islets have the potential to increase long-term insulin production in patients.
  • the system could have utility in T2D patients. While initial stages of T2D are characterised by insulin-resistance, approx.

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Abstract

L'invention concerne une composition pharmaceutique destinée à être utilisée dans la prévention et/ou le traitement du diabète, ladite composition comprenant un modulateur de la voie Glis3-Manf et une fraction de ciblage spécifique d'un tissu ou d'un organe d'un sujet, tel que le pancréas. L'invention concerne également des vecteurs viraux et des méthodes de prévention et/ou de traitement du diabète.
PCT/GB2023/050491 2022-03-02 2023-03-02 Thérapie génique glis3-manf pour la prévention ou le traitement du diabète Ceased WO2023166301A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090282495A1 (en) * 2008-04-30 2009-11-12 Licentia Ltd. Neurotrophic factor manf and uses thereof
WO2019218983A1 (fr) * 2018-05-16 2019-11-21 上海市同济医院 Vecteur de virus adéno-associé recombinant et son utilisation
US20210009645A1 (en) * 2018-03-29 2021-01-14 Helsingin Yliopisto C-terminal CDNF and MANF fragments, pharmaceutical compositions comprising same and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090282495A1 (en) * 2008-04-30 2009-11-12 Licentia Ltd. Neurotrophic factor manf and uses thereof
US20210009645A1 (en) * 2018-03-29 2021-01-14 Helsingin Yliopisto C-terminal CDNF and MANF fragments, pharmaceutical compositions comprising same and uses thereof
WO2019218983A1 (fr) * 2018-05-16 2019-11-21 上海市同济医院 Vecteur de virus adéno-associé recombinant et son utilisation

Non-Patent Citations (35)

* Cited by examiner, † Cited by third party
Title
BACKKAUFMAN, ANNU REV BIOCHEM, vol. 81, 2012, pages 767 - 793
BARRETT ET AL., NATURE GENETICS, vol. 41, 2009, pages 703 - 707
BONIFACIO ET AL., DIABETOLOGIA, vol. 60, 2017, pages 35 - 38
BUTLER ET AL., DIABETES, vol. 52, 2003, pages 102 - 110
CHELLAPPAN DINESH KUMAR ET AL: "Gene therapy and type 1 diabetes mellitus", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 108, 2 October 2018 (2018-10-02), pages 1188 - 1200, XP085532607, ISSN: 0753-3322, DOI: 10.1016/J.BIOPHA.2018.09.138 *
CHO ET AL., NATURE GENETICS, vol. 44, 2011, pages 67 - 72
CNOP ET AL., DIABETES, vol. 54, 2005, pages 97 - 107
CNOP ET AL., DIABETES, vol. 63, 2014, pages 1978 - 1993
CUNHA ET AL., CELL DEATH DIFFER, vol. 23, 2016, pages 1995 - 2006
DANILOVA TATIANA ET AL: "Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes", FRONTIERS IN PHYSIOLOGY, vol. 9, 16 October 2018 (2018-10-16), pages 1 - 21, XP055904459, DOI: 10.3389/fphys.2018.01457 *
DOOLEY ET AL., NATURE GENETICS, vol. 48, 2016, pages 519 - 527
DUPUIS ET AL., NATURE GENETICS, vol. 42, 2010, pages 105 - 116
EL-ASSAAD ET AL., ENDOCRINOLOGY, vol. 144, 2003, pages 4154 - 4163
FRIPONT ET AL., J VIS EXP, vol. 29, 2019, pages 143
HAKONEN ET AL., DIABETOLOGIA, vol. 61, 2018, pages 2202 - 2214
HALL ET AL., BMC MED, vol. 12, 2014, pages 103
HEIANZA, Y ET AL., DIABET MED, vol. 29, 2012, pages e279 - 285
IKEGAMI, ILAR J, vol. 45, 2004, pages 268 - 277
LAYBUTT ET AL., DIABETOLOGIA, vol. 50, 2007, pages 752 - 763
LI ET AL., DIABETES, vol. 62, 2013, pages 291 - 298
LINDAHL ET AL., CELL REPORTS, vol. 7, 2014, pages 366 - 375
LISTON ET AL., TRENDS MOL MED, vol. 23, no. 2, 2017, pages 181 - 194
LUPI ET AL., DIABETES, vol. 51, 2002, pages 1437 - 1442
MACK: "Remington's Pharmaceutical Sciences", 1982
MAEDLER ET AL., DIABETES, vol. 50, 2001, pages 1683 - 1690
MARIA LINDAHL ET AL: "MANF Is Indispensable for the Proliferation and Survival of Pancreatic β Cells", CELL REPORTS, vol. 7, no. 2, 1 April 2014 (2014-04-01), pages 366 - 375, XP055161920, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2014.03.023 *
MUNNEE ET AL., MEDICINE (BALTIMORE, vol. 95, 2016, pages e3006
NOGUEIRA ET AL., PLOS GENET, vol. 9, pages e1003532
RINCON ET AL., GENE THER, vol. 25, 2018, pages 83 - 92
ROIZEN ET AL., CURR DIAB REP, vol. 15, 2015, pages 102
SENEE ET AL., NATURE GENETICS, vol. 38, 2006, pages 682 - 687
SINGH ET AL., BIOMOLECULES, vol. 12, 2022, pages 1493
WICKER ET AL., J AUTOIMMUN, 2005, pages 29 - 33
WILKIN ET AL., DIABETES, OBESITY & METABOLISM, vol. 18, 2016, pages 3 - 5
ZHOU ET AL., NAT IMMUNOL, vol. 11, 2010, pages 136 - 140

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