Four of six men with Becker muscular dystrophy increased their six-minute walking distance after injections of follistatin genes into the thigh muscles of both legs
Update (March 24, 2015): Neurologist Jerry Mendell discusses the implications of this research in an approximately 20-minute podcast, part of the Nationwide Children's Hospital This Month in Muscular Dystrophy series.
Results from a trial involving injection of genes for the follistatin protein into the thigh muscles of both legs in six men with Becker muscular dystrophy (BMD) show the experimental treatment appears safe and and was associated with improvement in walking ability (distance walked in six minutes) in four of the six trial participants.
Neurologist Jerry Mendell at Nationwide Children's Hospital in Columbus, Ohio, was the principal investigator. Mendell co-directs the MDA neuromuscular disease clinic at Nationwide and is a longtime MDA research grantee, although the organization did not fund this particular trial.
"The results are encouraging for treatment of dystrophin-deficient muscle diseases," the authors write in their paper, which was published as an online preview Oct. 17, 2014 and in final form Nov. 18. The statement refers the dystrophin protein, which is entirely missing in the muscles of patients with Duchenne muscular dystrophy (DMD) and is present in a shortened, partially functional form in those with BMD.
Follistatin is a protein that counteracts the myostatin protein, which is a known inhibitor of muscle growth. It is hoped that administering follistatin genes will improve muscle growth and regeneration. Animal studies for which results were published in 2009 verified that follistatin injections can increase muscle size and strength with no apparent adverse effects.
Preliminary results for this human follistatin gene transfer trial, announced in November 2013, showed four of the BMD-affected, follistatin gene-treated trial participants had increased their walking distance at various time points and that no adverse events had occurred.
Gene transfer correlated with improvement in muscle appearance but not strength; four of six increased walking distance
In this trial, group 1 included three men with BMD who were ages 30, 35 and 37 and received four injections of follistatin genes into each of three thigh muscles. The genes were encased in the shells of type AAV1 viruses as a delivery vehicle. Both legs were injected in every trial participant.
A year later, two participants in group 1 showed robust improvement in the distance walked in six minutes, and one showed very modest improvement (not outside what would be expected from normal variability in BMD). There were no significant adverse events related to the gene transfer.
Based on the safety results from group 1, an additional three men with BMD — ages 24, 30 and 34 — were treated with a higher dose of follistatin genes per injection into the same leg muscles in both legs.
Six months after the injections, two participants showed increases in the distance walked in six minutes, while one showed a decrease. As in group 1, no significant adverse events were seen.
Interestingly, the investigators did not see an increase in thigh muscle strength after the gene transfer, despite seeing an increase in walking ability in some trial participants.
In four muscle biopsy samples taken 30 days prior to the injections and again at six months after the injections (one person refused a second biopsy and another had too much scarring to read the biopsy), there was an increase in the number of muscle fibers and in their size uniformity, as well as a decrease in scar tissue.
'Stage set' for larger trial in BMD
"The intramuscular injection of [follistatin genes inside viral shells] to BMD subjects in this clinical trial represents a successful proof-of-principle study with an excelelnt safety profile that mirrored preclinial findings," the investigators write. They say the study "sets the stage for a pivotal clinical trial [of follistatin gene transfer] for BMD patients" and that follistatin gene transfer "warrants consideration for studies in other forms of muscular dystrophy."