Pre-clinical development of SPY-DYS45-55, a CRISPR/Cas9 platform for Duchenne muscular dystrophy

MyoGene Bio is a startup dedicated to developing cutting edge genetic therapies for muscle diseases. In this proposal, the company will advance development of our potential therapeutic, SPY-DYS45-55, a CRISPR/Cas9 gene editing platform for Duchenne muscular dystrophy (DMD) in conjunction with research partners at UCLA. Duchenne is a devastating muscle wasting disorder with no cure that is caused by out-of-frame mutations in the DMD gene. SPY-DYS45-55 removes a mutational hotspot in DMD to restore the reading frame for half of all Duchenne patients by generating an in-frame exon 45-55 deletion. This deletion is associated with a very mild phenotype in human Becker muscular dystrophy patients. Systemic delivery of gene editing platforms to muscle represents a significant challenge. Certain serotypes of recombinant adenoassociated virus (AAV) have tropism to skeletal muscle and heart. However, the immune response to the virus prohibits repeated administration of AAV. Furthermore, pre-existing immunity in some individuals (anticipated to be present in up to 70% of adults), precludes their eligibility to take advantage of this treatment. The goal of this Fast Track proposal is to devise strategies to overcome these challenges. In Phase I, we will determine an optimal immunosuppression regimen that allows redosing of AAV in order to improve the efficacy and applicability of SPY-DYS45-55. In Phase II, we will assess the long-term functional benefit, toxicity, and off-target activity from single or multiple injections of AAV-SPY-DYS45-55 in our novel mouse model containing a mutated human DMD gene. Ultimately, these studies will generate the initial pre-clinical data needed to translate SPY-DYS45-55 to patients with Duchenne muscular dystrophy.