title: A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.
abstract: Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [3] Department of Neurology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [3] Department of Neurology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Malik
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [3] Department of Neurology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [2] Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Lowes
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [2] Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Alfano
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA [2] Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Berry
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meadows
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Braun
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Shontz
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Rouhana
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kelly Reed
authors.initials: KR
authors.lastname: Clark
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Xiomara Q
authors.initials: XQ
authors.lastname: Rosales
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Samiah
authors.initials: S
authors.lastname: Al-Zaidy
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Govoni
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.affiliation: Department of Radiology, Vascular and Interventional Radiology, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hogan
authors.affiliation: 1] Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000328:Adult; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D038702:Follistatin-Related Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C484258:DMD protein, human; D016189:Dystrophin; D038702:Follistatin-Related Proteins; C525911:MSTN protein, human; D055435:Myostatin