title: Sustained whole-body functional rescue in congestive heart failure and muscular dystrophy hamsters by systemic gene transfer.
abstract: BACKGROUND
  The success of muscular dystrophy gene therapy requires widespread and stable gene delivery with minimal invasiveness. Here, we investigated the therapeutic effect of systemic delivery of adeno-associated virus (AAV) vectors carrying human delta-sarcoglycan (delta-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a delta-SG gene mutation.
  
  
  RESULTS
  A single injection of double-stranded AAV serotype 8 vector carrying human delta-SG gene without the need of any physical or pharmaceutical interventions achieved nearly complete gene transfer and tissue-specific expression in the heart and skeletal muscles of the diseased hamsters. Broad and sustained (>12 months) restoration of the missing delta-SG gene in the TO-2 hamsters corrected muscle cell membrane leakiness throughout the body and normalized serum creatine kinase levels (a 50- to 100-fold drop). Histological examination revealed minimal or the absence of central nucleation, fibrosis, and calcification in the skeletal muscle and heart. Whole-body functional analysis such as treadmill running showed dramatic improvement, similar to the wild-type F1B hamsters. Furthermore, cardiac functional studies with echocardiography revealed significantly increased percent fractional shortening and decreased left ventricular end-diastolic and end-systolic dimensions in the treated TO-2 hamsters. The survival time of the animals was also dramatically extended.
  
  
  CONCLUSIONS
  Systemic gene transfer of delta-SG by the AAV serotype 8 vector could effectively ameliorate cardiac and skeletal muscle pathology, profoundly improve cardiac and whole-body functions, and significantly prolong the lifespan of the treated TO-2 hamsters.
authors.affiliation: Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Liqiao
authors.initials: L
authors.lastname: Zhou
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mori
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.forename: Chunping
authors.initials: C
authors.lastname: Qiao
authors.forename: Chunlian
authors.initials: C
authors.lastname: Chen
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D006224:Cricetinae; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006333:Heart Failure / Q000235:genetics / Q000628:therapy*; D008647:Mesocricetus; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000628:therapy*; D049031:Sarcoglycans / Q000172:deficiency* / Q000235:genetics
chemical_list: D049031:Sarcoglycans; D003402:Creatine Kinase