A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy

This was the first Phase 1/2a clinical trial of intramuscular gene therapy with the follistatin-344 (FS344) isoform in humans, conducted by the renowned Jerry R. Mendell's group at Nationwide Children's Hospital (Ohio). The therapeutic target was Becker muscular dystrophy (BMD) — a milder form of dystrophinopathy, in which patients retain partially functional dystrophin but exhibit progressive muscle weakness.

The mechanistic concept was to explore myostatin inhibition by follistatin as a strategy to promote muscle hypertrophy and repair. The chosen isoform was FS344 (which is processed to circulating FS315) — a version without heparan-sulfate affinity, with 10-fold lower activin affinity and greater safety regarding cardiotoxicity. The AAV1.CMV.huFS344 vector was bilaterally injected into the quadriceps muscles of 6 BMD patients in two dose cohorts: Cohort 1 (3 × 10¹¹ vg/kg/leg, n=3) and Cohort 2 (6 × 10¹¹ vg/kg/leg, n=3).

Results were clinically promising: in the 6-minute walk test (6MWT), two Cohort 1 patients improved by 58 and 125 meters respectively, and two Cohort 2 patients improved by 108 and 29 meters — in a disease characterized by progressive decline. Post-treatment muscle biopsies showed reduced endomysial fibrosis, decreased central nucleation (a sign of immature fibers), more normal fiber size distribution, and muscle hypertrophy, especially at the high dose. No serious adverse events were observed.

This work was a historical milestone: the first intramuscular gene therapy to demonstrate functional benefit in muscular dystrophy, validating follistatin as a viable clinical anti-myostatin tool. The trial led directly to the development of Phase 2 programs in Duchenne muscular dystrophy and sporadic inclusion body myositis, and influenced the current era of gene therapies for neuromuscular diseases.