title: Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes.
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 × 1011vg/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.
authors.affiliation: 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.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.affiliation: 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.
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
authors.forename: Samiah
authors.initials: S
authors.lastname: Al-Zaidy
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.affiliation: 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.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Lowes
authors.affiliation: 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.
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Alfano
authors.affiliation: 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.
authors.forename: Katherine
authors.initials: K
authors.lastname: Berry
authors.affiliation: 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.
authors.forename: Natalie
authors.initials: N
authors.lastname: Miller
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Yalvac
authors.affiliation: Biostatics Research Core, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dvorchik
authors.affiliation: Biostatics Research Core, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Moore-Clingenpeel
authors.affiliation: 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.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Church
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Shontz
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Choumpree
authors.initials: C
authors.lastname: Curry
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: McColly
authors.affiliation: Vascular and Interventional Radiology, Department of Radiology, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hogan
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D000818:Animals; D015415:Biomarkers; D001706:Biopsy; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D038681:Follistatin / Q000235:genetics*; D005500:Follow-Up Studies; D018628:Gene Dosage; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D020127:Recovery of Function; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D000070857:Walk Test
chemical_list: D015415:Biomarkers; D038681:Follistatin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: 6-min walk distance; 6-min walk test; Follistatin; adeno-associated virus; gene therapy; sporadic inclusion body myositis