Human α7 Integrin Gene (ITGA7) Delivered by Adeno-Associated Virus Extends Survival of Severely Affected Dystrophin/Utrophin-Deficient Mice

Hum Gene Ther. 2015 Oct;26(10):647-56. doi: 10.1089/hum.2015.062. Epub 2015 Aug 11.

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene. It is the most common, severe childhood form of muscular dystrophy. We investigated an alternative to dystrophin replacement by overexpressing ITGA7 using adeno-associated virus (AAV) delivery. ITGA7 is a laminin receptor in skeletal muscle that, like the dystrophin-glycoprotein complex, links the extracellular matrix to the internal actin cytoskeleton. ITGA7 is expressed in DMD patients and overexpression does not elicit an immune response to the transgene. We delivered rAAVrh.74.MCK.ITGA7 systemically at 5-7 days of age to the mdx/utrn(-/-) mouse deficient for dystrophin and utrophin, a severe mouse model of DMD. At 8 weeks postinjection, widespread expression of ITGA7 was observed at the sarcolemma of multiple muscle groups following gene transfer. The increased expression of ITGA7 significantly extended longevity and reduced common features of the mdx/utrn(-/-) mouse, including kyphosis. Overexpression of α7 expression protected against loss of force following contraction-induced damage and increased specific force in the diaphragm and EDL muscles 8 weeks after gene transfer. Taken together, these results further support the use of α7 integrin as a potential therapy for DMD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / administration & dosage
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics*
  • Dependovirus
  • Disease Models, Animal
  • Dystrophin / deficiency
  • Dystrophin / genetics*
  • Gene Expression Regulation
  • Genetic Therapy / methods
  • Humans
  • Integrin alpha Chains / administration & dosage
  • Integrin alpha Chains / biosynthesis
  • Integrin alpha Chains / genetics*
  • Mice
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / pathology
  • Muscular Dystrophy, Animal / therapy*
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / therapy*

Substances

  • Antigens, CD
  • Dystrophin
  • Integrin alpha Chains
  • integrin alpha7