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Advanced gene editing technologies to restore LAMA2 on merosin-deficient congenital muscular dystrophy type 1A

19th national competition for scientific and technical research

Rare diseases

Senior Researcher : Marc Güell Cargol

Research Centre or Institution : Universidad Pompeu Fabra. Barcelona

Abstract

We are developing a therapeutic strategy named Uni-large intended to treat the congenital muscular dystrophy type 1A (MDC1A), an early onset and life-threatening disease that affects 1 in 30.000 people. It is caused by mutations in the laminin alpha-2 (LAMA2) which exceeds the size limit of AAV vectors, so it is necessary to develop alternative therapeutics. In addition, despite this important progress, ‘in situ’ mutation correction still faces important safety and efficacy challenges. Homology driven repair (HDR) methods, which are usually used for small allele editing, are still remarkably inefficient for most primary tissues or large edits.

We will develop and deploy Uni-large, a new generation of medicines combining the precision of modern CRISPR/cas9 and the efficiency of viral vectors established in clinic. Uni-large will contains all elements to perform precise gene delivery: a newly developed RNA-directed transposase or integrase, and the payload DNA to be delivered. Also, all elements will be co-optimized. Appropriate mouse models will be used to deploy the novel gene delivery strategies to restore LAMA2 functionality. We will demonstrate the efficacy on 'ex vivo' editing of bone marrow using lentiviruses, and 'in vivo' directly on the muscle using nanoparticles.

Uni-Large addresses multiple challenges that prevent wider deployment of gene editing technologies. It allows to insert multikilobase genome fragments, does not depend on HDR (often limiting efficacy), and it is potentially safer than competing technologies (absence of double stranded breaks, reduced insertional mutagenesis).

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