Published Online
on October 17, 2005

A more recent version of this article appeared on October 25, 2005

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Submitted on May 31, 2005
Revised on July 2, 2005
Accepted on ,

Sustained Whole-Body Functional Rescue in Congestive Heart Failure and Muscular Dystrophy Hamsters by Systemic Gene Transfer

Tong Zhu MD, PhD, Liqiao Zhou VMD, Satsuki Mori MD, Zhong Wang MD, PhD, Charles F. McTiernan PhD, Chunping Qiao MD, PhD, Chunlian Chen MD, Dao Wen Wang MD, PhD, Juan Li MD, and Xiao Xiao PhD^*

From the Molecular Therapy Laboratory, Department of Orthopedic Surgery (T.Z., L.Z., Z.W., C.Q., C.C., J.L., X.X.), Department of Molecular Genetics and Biochemistry (X.X.), and Cardiovascular Institute (S.M., C.F.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pa, and the Department of Cardiology (C.C., D.W.W.), Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

^* To whom correspondence should be addressed. E-mail: xiaox{at}pitt.edu.

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 -sarcoglycan (-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a -SG gene mutation.

Methods and Results--A single injection of double-stranded AAV serotype 8 vector carrying human -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 -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 -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.

Key words: viruses • cardiomyopathy • gene therapy

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