DS0404 - Innovation biomédicale

Systemic injection in the Golden Retriever Muscular Dystrophy dog of a recombinant adeno-associated virus encoding for the canine µdystrophin: Determination of the therapeutic dose that improves skeletal muscle function and cardiac performances. – µdys

Submission summary

- µdys is a program primarily aimed to cure the devastating Duchenne muscular dystrophy (DMD) by expressing a shorter but functional dystrophin polypeptide called “µdystrophin”. DMD is the most frequent progressive muscle degenerative disease, affecting approximately one in 3,500 male births. DMD is caused by deletions or mutations in the gene encoding dystrophin. Dystrophin provides a mechanical and functional link between the cytoskeleton of the muscle fiber and the extracellular matrix. The absence of dystrophin causes fiber degeneration, inflammation, necrosis and replacement of muscle with scar and fat tissue, resulting in progressive muscle weakness and premature death. There is no cure or effective treatment available for DMD.
- Today, there are essentially two gene therapy strategies for DMD: (i) constitutive expression of antisense oligonucleotides to promote exon skipping, which is amenable to certain mutations, and; (ii) constitutive expression of a cDNA coding for a functional micro dystrophin (µdys).
µdys is a gene therapy translational program since we have evidence from preliminary data that our advanced therapy medicinal product (ATMP) restores skeletal muscle function in a large animal model, the Golden Retriever Muscular Dystrophy (GRMD) dog.
- A gene therapy product is made of 2 components: (i) the encapsidated recombinant DNA, which defines the expression cassette that provide the therapeutic benefit(s), and; (ii) the viral capsid, which allows proper gene transfer and to a certain extent, tissue tropism. Translating from the research to the clinic such complex ATMP consists in evaluating a combination of effects between the two components of the product. This is an important aspect in gene therapy translational programs and explains why despite that we have collected evidence for phenotypic rescue with our candidate ATMP, we have anticipated a couple of scenarios for alternative ATMP variants provided through a “Decisional and organizational” chart.
If granted, the ANR translational grant will support: (i) the dose determination in the GRMD dog model; (ii) the definition of an optimized downstream process of our ATMP that will enhance its potency; (iii) the definition of the best capsid to allow wide spread gene transfer to large territories of skeletal muscles and also myocardium.
- It is a collaborative project involving 4 entities on the territory, UMR1089 at the University Hospital in Nantes, the Myology Institute at the University Hospital of Pitié Salpétrière in Paris and GENETHON in Evry. This consortium has been working together since January 2009 on a complementary translational Duchenne gene therapy program using the exon skipping approach. This has progressed significantly since the Investigational Medicinal Product Dossier (IMPD) is close to be submitted to the French regulatory agency for a Phase I/II trial in non-ambulant Duchenne patients.
- Since exon skipping cannot address all Duchenne patients, the µdys program was initiated among the same consortium but deferred due to ressource limitation. We expect to submit a µdystrophin IMPD in 2017 after the regulatory toxicology study will be completed.
- The research asset of the different teams composing the consortium is the impressive accumulation of know-how and expertise in the design, manufacturing and validation of vectors for gene therapy. New developments through the µdys program will directly contribute to the promotion and competitive access to preclinical and clinical trials, as the most immediate and practical way of valorization. Successful access to the ANR resource will complement our current effort essentially dispatched between AFM and INSERM. To achieve these goals, a consortium agreement will be put in place between the partners of the project, where each partner will grant the others access to all available background knowledge necessary for the performance of the project.

Project coordination

Philippe Moullier (Thérapie Génique translationnelle des maladies neuromusculaires et de la Rétine)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


AIM Association Institut de Myologie
Inserm UMR1089 Thérapie Génique translationnelle des maladies neuromusculaires et de la Rétine

Help of the ANR 315,949 euros
Beginning and duration of the scientific project: September 2014 - 24 Months

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