Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector

Abstract

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.

Persistent expression of canine factor IX in hemophilia B canines

“…29,30 A recent report employing intravenous rAAV injection at the time of histamine-induced endothelial permeability demonstrated the transduction of the distal hindlimb musculature. 45 These results strongly imply that improvements in vector delivery and protein expression are achievable. Therefore, safe and efficient transduction seems achievable for AAV-mediated hemophilia B gene therapy.…”

Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product

“…The results of immunosupression in later stages by anti-CD4 antibody treatment also support the hypothesis that immune response has been concerned in the AAV-vector mediated gene transfer into mdx skeletal muscle. Several groups have previously demonstrated effective AAV vector-mediated gene transfer into skeletal muscles of mdx mice, 28 ␦-sarcoglycandeficient hamsters (Bio 14.6) 21,22 and ␥-sarcoglycandeficient mice. 23 On the other hand, Cordier et al 24 have shown that an AAV vector driven by CMV promoter elicits strong cellular and humoral immune responses to the transgene product after intramuscular injection into ␥-sarcoglycan-null mice.…”

“…[16][17][18]20 Thus, AAV vectors may be applicable to treatment of inherited neuromuscular disorders such as DMD. In fact, the AAV vector has been successfully introduced into ␦-sarcoglycan-deficient hamsters (Bio 14.6) 21,22 and ␥-sarcoglycan-deficient mice, 23 animal models of limb girdle muscular dystrophies (LGMD). A recent report, however, showed lower levels of transgene expression together with substantial immune response to the therapeutic transgene product in ␥-sarcoglycan-null mice.…”

Electrotransfer of naked DNA in the skeletal muscles of animal models of muscular dystrophies

“…Recent studies documented the administration of various vectors through the vascular route following transient ischemia, chemically induced vasodilatation, 49 or under high physical pressure. 50 The focused ultrasound technology should also be considered. 51 Therefore, naked DNA transfer could be improved by the coupling of one of these approaches to the electrotransfer methodology.…”