The potential of adeno-associated viral vectors for gene delivery to muscle tissue

Abstract

Introduction Muscle-directed gene therapy is rapidly gaining attention primarily because muscle is an easily accessible target tissue and is also associated with various severe genetic disorders. Localized and systemic delivery of recombinant adeno-associated virus (rAAV) vectors of several serotypes results in very efficient transduction of skeletal and cardiac muscles, which has been achieved in both small and large animals, as well as in humans. Muscle is the target tissue in gene therapy for many muscular dystrophy diseases, and may also be exploited as a biofactory to produce secretory factors for systemic disorders. Current limitations of using rAAVs for muscle gene transfer include vector size restriction, potential safety concerns such as off-target toxicity and the immunological barrier composing of pre-existing neutralizing antibodies and CD8+ T-cell response against AAV capsid in humans. Areas covered In this article, we will discuss basic AAV vector biology and its application in muscle-directed gene delivery, as well as potential strategies to overcome the aforementioned limitations of rAAV for further clinical application. Expert opinion Delivering therapeutic genes to large muscle mass in humans is arguably the most urgent unmet demand in treating diseases affecting muscle tissues throughout the whole body. Muscle-directed, rAAV-mediated gene transfer for expressing antibodies is a promising strategy to combat deadly infectious diseases. Developing strategies to circumvent the immune response following rAAV administration in humans will facilitate clinical application.

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“…Viral vectors are preferred for gene delivery to brain cells as well as other cell types including muscles (Wang et al., 2014), cardiac cells (Katz et al., 2013), and cancer cells (Cerullo et al, 2010). Viral vectors exploit the ability of a virus to infect mammalian cells and use of host machinery to produce viral proteins.…”

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“…Drug screens to identify ways to up-regulate the dystrophin homologue utrophin have also been of major focus in academic and commercial ventures [1,24]. Gene therapy has been heavily focused on delivering micro-dystrophin genes (due to gene packaging size limitations of appropriate vectors) into muscle using adeno-associated viruses (AAV) [1,4]. More recently, the size limitation issue of AAV has been overcome by implementing a triple-AAV vector system to successfully express full-length dystrophin in mice [25,26].…”

“…Satellite cells make up 2–7% of the nuclei in adult murine muscle, are higher in oxidative muscles and notably, reside in close proximity to blood capillaries [1,4,24]. They display several cell surface and nuclear biomarkers foremost being the expression of the paired box transcription factors Pax7 and/or Pax3 [1,4,9]. Pax7 is the canonical SC biomarker expressed across several species in both quiescent and proliferating SCs (Fig.…”