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Targeted Genetic Manipulation of Muscle Stem Cells in vivo Towards New Treatment Strategies Against Muscular Dystrophies

Objective

Duchenne Muscular Dystrophy (DMD) is a devastating disorder affecting 1/5000 male births, leading to progressive muscle wasting and early mortality. Current gene therapy strategies for muscular dystrophies have shown partial benefits but remain limited by systemic toxicity, inefficient transduction of muscle stem cells (MuSCs), and a continuous turnover of muscle fibres that progressively reduces the therapeutic effect over time. To address these bottlenecks, we propose a receptor-targeted gene delivery platform based on adeno-associated viruses (AAVs) engineered to selectively transduce MuSCs. Restoring Dystrophin expression in this rare but regenerative cell population may allow durable, stem cell-driven correction of muscle fibres in DMD.
Building on strong preliminary findings, we have identified candidate MuSC-enriched cell-surface markers and will generate high-affinity ligands (DARPins) against these targets. DARPins will be incorporated into AAV capsids blinded to their natural receptors, creating “DART-AAVs” targeting MuSCs through defined receptors while reducing transduction of non-target cells. DART-AAVs will be combined with CRISPR/Cas9 genome editing tools to restore Dystrophin expression in DMD mouse models. This PoC will deliver first-generation MuSC-targeted DART-AAV vectors for in vivo validation. We will also refine a translational strategy including IP protection, market analysis, and engagement with industrial and clinical stakeholders.
By focusing on MuSC targeting, this approach aims to reduce off-target toxicities, lower required viral loads, and exploit the intrinsic regenerative capacity of stem cells to sustain long-term muscle repair. We aim to deliver a MuSC-targeted gene delivery platform with strong clinical and commercial potential, for DMD and related muscle diseases. If successful, our PoC will pave the way for novel cell-type-focused gene therapies not only for DMD but also for other degenerative diseases.

Fields of science (EuroSciVoc)

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

(opens in new window) ERC-2026-POC

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Host institution

INSTITUT PASTEUR
Net EU contribution
€ 150 000,00
Address
RUE DU DOCTEUR ROUX 25-28
75724 Paris
France
Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Total cost
No data

Beneficiaries (1)