Abstract
Various characteristics of adeno-associated virus (AAV)-based vectors with long-term safe expression have made it an exciting transduction tool for clinical gene therapy of Duchenne muscular dystrophy (DMD). Although host immune reactions against the vector as well as transgene products were detected in some instances of the clinical studies, there have been promising observations. Methods of producing AAV vectors for considerable in vivo experimentation and clinical investigations have been developed and a number of studies with AAV vector-mediated muscle transduction were attempted. Notably, an intravenous limb perfusion transduction technique enables extensive transgene expression in the skeletal muscles without noticeable adverse events. Furthermore, cardiac transduction by the rAAV9-microdystrophin would be promising to prevent development of cardiac dysfunction. Recent achievements in transduction technology suggest that long-term transgene expression with therapeutic benefits in DMD treatment would be achieved by the rAAV-mediated transduction strategy with an adequate regimen to regulate host immune response.
Highlights
Duchenne muscular dystrophy (DMD) is the most common form of childhood muscular dystrophy.DMD is an X-linked recessive disorder with an incidence of one in 3,500 live male births [1]
Neo-antigens introduced by associated virus (AAV) vectors evoke significant immune reactions in DMD muscle, since increased permeability of the DMD muscle allows leakage of the transgene products from the dystrophindeficient sarcolemma of muscle fibers [79]. rAAV2 transfer into skeletal muscles of normal dogs resulted in low levels of transient expression, together with intense cellular infiltration, and the marked activation of cellular and humoral immune responses [77]
Our study showed that MyD88 and co-stimulating factors, such as CD80, CD86 and type I interferon, are up-regulated in both rAAV2and rAAV8-transduced dog dendritic cells (DCs) (Figure 3A) [51]
Summary
Duchenne muscular dystrophy (DMD) is the most common form of childhood muscular dystrophy. A placebo-controlled, double-blind study of 146 ambulant DMD patients who received cyclosporine-A or placebo alone and in combination with prednisone demonstrated no difference in muscle strength and functional abilities between the treatment groups [7]. Its efficacy in mdx mice is similar to gentamicin, producing dystrophin expression in 20-25% of muscle fibres [8] With these results, a double-blind, randomised, multicentric study was carried out on. By inducing the skipping of specific exons during mRNA splicing, antisense compounds correct the open reading frame of the DMD gene and to restore truncated yet functional dystrophin expression in vitro [9]. A study targeting the exon 51 in seven DMD patients (AVI-4658) showed that those had received higher doses (0.9 mg) produced the dystrophin at 22%–32% levels of normal in. No signs of toxicity were observed, while a previous study performed on non-human primates had shown tubular degeneration in the kidneys
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