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Mol Ther. 2017 Apr 5;25(4):870-879. doi: 10.1016/j.ymthe.2017.02.015. Epub 2017 Mar 6.

Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes.

Author information

1
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA. Electronic address: jerry.mendell@nationwidechildrens.org.
2
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA.
3
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
4
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA; Clinical Therapies, Nationwide Children's Hospital, Columbus, OH 43205, USA.
5
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
6
Biostatics Research Core, Nationwide Children's Hospital, Columbus, OH 43205, USA.
7
Vascular and Interventional Radiology, Department of Radiology, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Abstract

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.

KEYWORDS:

6-min walk distance; 6-min walk test; Follistatin; adeno-associated virus; gene therapy; sporadic inclusion body myositis

PMID:
28279643
PMCID:
PMC5383643
DOI:
10.1016/j.ymthe.2017.02.015
[Indexed for MEDLINE]
Free PMC Article

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