title: Follistatin gene delivery enhances muscle growth and strength in nonhuman primates.
abstract: Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.
authors.affiliation: Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Janaiah
authors.initials: J
authors.lastname: Kota
authors.forename: Chalonda R
authors.initials: CR
authors.lastname: Handy
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Haidet
authors.forename: Chrystal L
authors.initials: CL
authors.lastname: Montgomery
authors.forename: Amy
authors.initials: A
authors.lastname: Eagle
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.forename: Danielle
authors.initials: D
authors.lastname: Tucker
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Shilling
authors.forename: Walter R
authors.initials: WR
authors.lastname: Therlfall
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
authors.forename: Steven E
authors.initials: SE
authors.lastname: Weisbrode
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
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: D017398:Alternative Splicing; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D038681:Follistatin / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008252:Macaca fascicularis / Q000254:growth & development / Q000502:physiology*; D053580:Muscle Strength / Q000235:genetics*; D018482:Muscle, Skeletal / Q000254:growth & development*
chemical_list: D038681:Follistatin