Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector.
Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.
Greelish
J P
JP
Department of Surgery, University of Pennsylvania Health System, Philadelphia 19104, USA.
Su
L T
LT
Lankford
E B
EB
Burkman
J M
JM
Chen
H
H
Konig
S K
SK
Mercier
I M
IM
Desjardins
P R
PR
Mitchell
M A
MA
Zheng
X G
XG
Leferovich
J
J
Gao
G P
GP
Balice-Gordon
R J
RJ
Wilson
J M
JM
Stedman
H H
HH
D000818:Animals; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006632:Histamine / Q000627:therapeutic use*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000627:therapeutic use*; D009137:Muscular Dystrophy, Animal / Q000628:therapy*; D010477:Perfusion; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000627:therapeutic use; D049031:Sarcoglycans; D012508:Sarcolemma / Q000473:pathology
D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D049031:Sarcoglycans; D006632:Histamine