Keywords: drug delivery, gene delivery, nanoparticle
Summary:There is considerable interest in the therapeutic potential of CRISPR/Cas9-mediated gene editing to treat a wide variety of genetic diseases; however, clinically viable delivery of CRISPR/Cas9 components presents an obvious challenge. Effective and safe delivery of CRISPR/Cas9 components, whether based on viral or non-viral delivery vehicles, would require specific targeting of a tissue or cell type; and brief half-life in order to minimize potential off-target activity and innate and humoral immune responses. In addition, the ability to re-administer the therapy to attain stable, therapeutically relevant levels of gene editing would be an advantage. With these requirements in mind, we have explored the use of lipid nanoparticles (LNPs) for delivery of CRISPR/Cas9 components to the mouse liver to mediate editing of target DNA within hepatocytes. Results demonstrate that therapeutically meaningful levels of in vivo CRISPR/Cas9-mediated gene editing can be obtained with a completely synthetic and scalable single-agent LNP system, and suggest that the treatment of liver-based genetic disease with CRISPR/Cas9 will be clinically viable.