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

PROJECT SUMMARY MyoGene Bio is a startup dedicated to developing cutting edge genetic therapies for muscle diseasesIn this proposalthe company will advance development of our potential therapeuticSPY DYSa CRISPR Casgene editing platform for Duchenne muscular dystrophyDMDin conjunction with research partners at UCLADuchenne is a devastating muscle wasting disorder with no cure that is caused by out of frame mutations in the DMD geneSPY DYSremoves a mutational hotspot in DMD to restore the reading frame for half of all Duchenne patients by generating an in frame exondeletionThis deletion is associated with a very mild phenotype in human Becker muscular dystrophy patientsSystemic delivery of gene editing platforms to muscle represents a significant challengeCertain serotypes of recombinant adenoassociated virusAAVhave tropism to skeletal muscle and heartHoweverthe immune response to the virus prohibits repeated administration of AAVFurthermorepre existing immunity in some individualsanticipated to be present in up toof adultsprecludes their eligibility to take advantage of this treatmentThe goal of this Fast Track proposal is to devise strategies to overcome these challengesIn Phase Iwe will determine an optimal immunosuppression regimen that allows redosing of AAV in order to improve the efficacy and applicability of SPY DYSIn Phase IIwe will assess the long term functional benefittoxicityand off target activity from single or multiple injections of AAV SPY DYSin our novel mouse model containing a mutated human DMD geneUltimatelythese studies will generate the initial pre clinical data needed to translate SPY DYSto patients with Duchenne muscular dystrophy PROJECT NARRATIVE In this proposalMyoGene Bio will further develop our productSPY DYSa gene editing platform that permanently removes genetic mutations for approximately half of all Duchenne muscular dystrophy patientsSince Duchenne has no cure and only limited treatmentsSPYDYSoffers a potential therapy for a large cohort of Duchenne patientsAdditionallythe knowledge that will be obtained about redosing adeno associated virusAAVSPY DYSwill have far reaching implications for improving the efficacy and safety of other AAV based therapies