PROJECT SUMMARY
Comparison of single versus dual vector delivery of AAV-SPY-DYS45-55 for Duchenne muscular
dystrophy
MyoGene Bio is a startup dedicated to developing cutting edge therapies for muscle diseases. In this
proposal, MyoGene Bio, in conjunction with research partners at UCLA, will advance development of our
CRISPR/Cas9 gene editing therapeutic, SPY-DYS45-55, for Duchenne muscular dystrophy (DMD).
Duchenne is a devastating muscle wasting disorder with no cure that is typically caused by out-of-frame
mutations in the DMD gene. SPY-DYS45-55 removes a mutational hotspot in the DMD gene by generating
an in-frame exon 45-55 deletion to restore the reading frame for half of all Duchenne patients. 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 adeno-associated virus (AAV) have tropism to skeletal muscle and heart.
However, due to the large size of SpCas9, dual vectors are required for delivery of SPY-DYS45-55. Dual
AAV vectors could be problematic in that they may require higher amounts of virus to be injected, may be
less efficient, and may increase manufacturing costs. These higher doses may be more likely to lead to
serious adverse events. Thus, an alternative approach is to utilize SaCas9 (~1kb smaller) in a single
vector. Here, AAV-SPY-DYS45-55 will be dosed as either a single or dual vector approach in our novel
mouse model containing a mutated human DMD gene and dystrophin restoration and preliminary
functional improvement will be assessed. Ultimately, these studies will generate important data for how
to optimally deliver and translate SPY-DYS45-55, and potentially other CRISPR-based therapies, to
patients with Duchenne muscular dystrophy.
