Syn-NES-jRGECO1b AAV (Serotype 9)

The development of adeno-associated viruses (AAVs) as gene delivery vectors has made great strides over the past few decades. The success of AAV as a gene delivery vector is attributed to its multiple properties, including its lack of pathogenicity, favorable safety profile, and ease of production to clinical grade. In addition, the minimal genome required for AAV replication allows replacement of large portions of the genome with foreign DNA, resulting in packaging capacities of up to 4.7 kb for standard AAV vectors, or about half that of self-complementary AAV vectors. Importantly, AAV vectors exhibit broad species tropism and are malleable. To date, approved AAV-based drugs and most clinical trials utilizing AAV vectors have been designed to complement defective genes with new, effective copies, but many studies have investigated the use of AAV for the delivery of non-self therapeutic genes.

While the degree of tropism for tissue types may vary between serotypes, the transduction spectrum of AAV is fairly broad, with no clear specificity for tissue/cell types and overlap in tropism between serotypes. Despite the lack of specificity and off-target tissue transduction, native AAV serotypes have been used in many clinical studies. AAV2 has been used to treat cystic fibrosis and to deliver the neuropeptide, GAD, and AADC genes for Parkinson's disease. AAV4 has been used to deliver the RPE65 gene into RPE cells, providing clinical benefit. AAV8 has been used in multiple trials, such as a Phase I/II clinical trial for X-linked retinitis pigmentosa, which showed sustained visual improvement in 6 of 18 patients, as well as X-linked myotubular myopathy and glycogen storage disease type Ia. AAV9 has been used in multiple trials to treat patients with mucopolysaccharidoses types I, II, and IIIA, Parkinson's disease, Gaucher disease, and neuronal ceroid lipofuscinosis (NCL).