Gene Therapy for Treatment of Duchenne Muscular Dystrophy: Race to Bring Therapy to Market (Sarepta, Pfizer & Solid Biosciences)

Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by dystrophin gene (DMD) mutations. The Estimated incidence of DMD worldwide is 1 in 5000 live male births. 

The DMD gene encodes for the cytoskeletal protein dystrophin. Dystrophin is a 427-kDa cytoskeletal protein required for sarcolemmal stability. The deficiency of the protein leads to susceptibility to repeated cycles of necrosis and regeneration as well as diminished regenerative muscle capacity, resulting in muscle fibrosis. DMD is a progressive disorder with the loss of ambulation between age 9 and 14 years, followed by respiratory complications and cardiac function decline, and ultimately death.

Gene Therapy for DMD

The dystrophin is one of the large proteins, and the packaging of cDNA that encodes the full protein into the AAV vector (size limit- 4,500 to 5000 bp) is not possible. Evidence suggests that the truncated dystrophin are partially functional, and maybe efficacious in DMD subjects by partially rescuing the disease pathology (Becker Muscular Dystrophy like phenotype). The patients with Becker Muscular Dystrophy have partial loss of muscle function but able to work and live longer without cardiac or respiratory complications. 

Clinical Stage Gene Therapy for DMD
- AAVrh74.MHCK7.micro-dystrophin (Serapta Therapeutics- SRP- 9001)
- AVV9-minidystrophin (Pfizer- PF-06939926)
- AAV9- microdystrophin (Solid Biosciences- SGT-001 )

Gene Therapies in Pre-clinical Stage

Figure Reference: Nature