rInsulin2-SaCas9HF AAV (Serotype 9)

The development of adeno-associated viruses (AAVs) as gene delivery vectors has made significant progress over the past few decades. Recently, AAV-based drugs Luxturna (a treatment for inherited blindness) and Zolgensma (a treatment for spinal muscular dystrophy) have been approved by the U.S. Food and Drug Administration (FDA) for use in the United States, marking an important milestone in the establishment of AAV-based therapies in the clinic. The success of AAV as a gene delivery vector is attributed to its multiple properties, including its non-pathogenicity, good safety profile, and ease of production to clinical grade. In addition, the extremely low genome size required for AAV replication allows replacement of large portions of the genome with foreign DNA, allowing standard AAV vectors to have a packaging capacity of up to 4.7 kb, which is approximately half that of self-complementary AAV vectors. Importantly, AAV vectors exhibit a wide range of species tropism and are plastic. To date, approved AAV-based drugs and most clinical trials utilizing AAV vectors are designed to complement defective genes with new effective copies, but many studies have explored the use of AAV for the delivery of non-self therapeutic genes.

One promising application of AAV-based therapeutics is the delivery of gene-editing enzymes to repair defective genes. In preclinical studies, several groups have reported the efficient editing of genes in animal models using AAV-delivered CRISPR/Cas9 technology to treat diseases such as Duchenne muscular dystrophy, hypercholesterolemia, and urea cycle disorders. Similarly, the use of gene-editing technologies to inactivate and eliminate viral reservoirs that cause persistent/chronic infections has recently attracted much attention. In fact, recent reports of the elimination of viral genomes using macrophage nucleases and CRISPR/Cas9 in animal models of chronic infection with HSV and HIV, respectively, support the use of AAV vectors to treat chronic viral infections. AAV-mediated delivery of antiviral therapies is not limited to gene-editing enzymes. For example, several groups have used AAV vectors to deliver other antiviral therapies such as RNA interference molecules and virus-neutralizing antibodies.