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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



We are developing a therapeutic strategy intended to treat the congenital musculardystrophy type 1A (MDC1A), an early onset and life-threatening disease. 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, especially in this disease where mutations are aleatory and not well characterized. 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 have been developing and deploying a new generation of medicines combining the precision of modern CRISPR/cas9 and the efficiency of insertional technologies such as transposases. This technology contains all elements to perform precise gene delivery: a newly developed RNA-directed transposase, and the payload DNA to be delivered. Also, all elements were co-optimized. Appropriate mouse models were used to deploy the novel gene delivery strategies. We intended to demonstrated the efficacy on ex vivo editing of bone marrow using lentiviruses, and in vivo directly on the muscle using nanoparticles. This methodology 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. 

The prototype of a “programmable transposase” was successfully developed using CRISPR and hyperactive PiggyBac transposase modified technologies and published in a high impact factor journal. It was deployed using Lipid Nanoparticles in vivo with successful expression and insertion of luciferase gene. Lama2 gene was previously deployed into the dystrophic mouse model with in vivo JetPEI vehicle with successful Lama2 expression in plasma high copy number was detected in liver, as a probe of insertion.

Bone marrow from WT mice was infected with Lama2 encoding lentivirus and successfully transplanted into mouse model -/- mice. Increase in lifespan and strength (grip assay) was detected. We obtained positive results on LAMA2 lentiviral transduction on the bone marrow. We managed to assemble the virus and treat two cohort of animals. We obtained a remarkable MDC1A amelioration. 


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