Abstract
Adeno-associated viral (AAV) vector-mediated gene replacement for the treatment of muscular dystrophy represents a promising therapeutic strategy in modern medicine. One major obstacle in using AAV vectors for in vivo gene delivery is the development of host immune responses to the viral capsid protein and transgene products as evidenced in animal models and human trials for a range of genetic diseases. Here, we review immunity against AAV vector and transgene in the context of gene delivery specific to muscles for treating muscular dystrophies and non-muscle diseases in large animal models and human trials, factors that influence the intensity of the immune responses, and immune modulatory strategies to prevent unwanted immune responses and induce tolerance to the vector and therapeutic gene for a successful gene therapy.
Highlights
Muscular dystrophies are a group of heterogeneous diseases that primarily affect striated muscles throughout the body
Studies focusing on adenoviral (Ad), retroviral, and adeno-associated viral (AAV) vectors have shown that delivery via these vectors of full-length or truncated but functional genes improves the disease phenotype in animal models (Gregorevic and Chamberlain, 2003; Dudley et al, 2004; Gregorevic et al, 2004; Li et al, 2005; Liu et al, 2005), which has led to initiation of early phase clinical trials (Mendell et al, 2009, 2010a)
This review will focus on recent reports of immunity to AAV capsid proteins and transgene products in large animal models and human trials of muscular dystrophy, as well as strategies that are needed for a successful in vivo gene transfer to muscle
Summary
Muscular dystrophies are a group of heterogeneous diseases that primarily affect striated muscles throughout the body. Many of these myopathies are caused by mutations in genes that encode structural proteins which link the cytoskeleton of muscle fibers to the extracellular matrix. This review will focus on recent reports of immunity to AAV capsid proteins and transgene products in large animal models and human trials of muscular dystrophy (summarized in the Table 1), as well as strategies that are needed for a successful in vivo gene transfer to muscle
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