title: Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model.
abstract: Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promising therapies: micro-dystrophin gene replacement and muscle enhancement with follistatin, a potent myostatin inhibitor. Individual treatments with micro-dystrophin and follistatin demonstrated marked improvement in mdx mice but were insufficient to fully restore muscle strength and response to injury to wild-type levels. Strikingly, when combined, micro-dystrophin/follistatin treatment restored force generation and conferred resistance to contraction-induced injury in aged mdx mice. Pre-clinical studies with miniature dystrophins have failed to demonstrate full correction of the physiological defects seen in mdx mice. Importantly, the addition of a muscle enhancement strategy with delivery of follistatin in combination with micro-dystrophin gene therapy completely restored resistance to eccentric contraction-induced injury and improved force. Eccentric contraction-induced injury is a pre-clinical parameter relevant to the exercise induced injury that occurs in DMD patients, and herein, we demonstrate compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.
authors.affiliation: Department of Pediatrics.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Shontz
authors.forename: Benjamin
authors.initials: B
authors.lastname: Canan
authors.forename: Chrystal L
authors.initials: CL
authors.lastname: Montgomery
authors.forename: Danielle
authors.initials: D
authors.lastname: Griffin
authors.forename: Kristin
authors.initials: K
authors.lastname: Heller
authors.forename: Leah
authors.initials: L
authors.lastname: Schmelzer
authors.forename: Chalonda
authors.initials: C
authors.lastname: Handy
authors.forename: K Reed
authors.initials: KR
authors.lastname: Clark
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D038681:Follistatin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009137:Muscular Dystrophy, Animal; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy
chemical_list: D016189:Dystrophin; D038681:Follistatin