CAG-FLEX-CaMPARI AAV (Serotype 8)

Adeno-associated viruses (AAVs) belong to the Dependovirus genus of the single-stranded DNA (ssDNA) Parvoviridae family and are promising gene transfer vectors due to their ability to transduce both non-dividing and dividing cells. These viruses require the helper functions of adenovirus or herpes simplex virus to produce an effective infection, but this infection has not been associated with any disease or pathogenic outcome. Several AAV serotypes have been tested in clinical gene therapy trials, with AAV2 being the best characterized and most used, although several other serotypes, including AAV1, AAV1/2 hybrids, AAV6, AAV8, and AAVrh10, have also been used in clinical studies. AAV vectors exhibit a broad tissue tropism, with some being able to transduce certain tissues more efficiently than others. For example, in mouse liver, AAV8 has repeatedly been shown to have better transduction efficiency than other serotypes. The first reported successful treatment of hemophilia A in mice was with an AAV8 vector, and AAV8 is now used in human clinical trials to deliver factor IX to patients with hemophilia B. Comparative studies of AAV2, AAV6, and AAV8 vectors in the liver have shown that AAV8 is a more efficient sensor due to its rapid shedding of the viral capsid, which allows for more rapid initiation of dsDNA production during genome replication. This phenotype results in a 4- to 10-fold increase in transduction of mouse hepatocytes by AAV8 vectors compared to AAV2. The presence of neutralizing antibody responses to AAV capsids is known to effectively block gene transfer in large animal models, which is also seen in human patients. The human population has documented high neutralizing antibody titers already to the more common AAV2. In contrast, AAV8 has the lowest seroprevalence in humans (<40%) compared to AAV1, AAV2, AAV5, AAV6, and AAV9, highlighting the potential use of AAV8 vectors for patients who have been exposed to other serotypes.