AAV9-aMHC-Null

Adeno-associated virus (AAV)-mediated gene delivery has been demonstrated to be a safe and reliable method for long-term expression of transgenes in the central nervous system (CNS). Wild-type AAV contains a 4.7 kb genome consisting of rep and cap genes, encoding 4 replication proteins and 3 capsid proteins, respectively, flanked by two 145 bp inverted terminal repeats (ITRs). The capsid is a major determinant of AAV tropism and transduction properties. Different AAV capsid serotypes utilize specific cellular receptors and coreceptors for attachment and internalization into host cells. For example, AAV2 and 3 bind primarily to heparin sulfate proteoglycans; AAV1, 4, 5, and 6 bind to sialylated glycoproteins; AAV9 binds to galactose, while AAV8 has no known major receptor.

The capsid proteins of various AAV clades share approximately 45% amino acid similarity, with the most divergent serotypes being AAV2/4 and AAV2/5. These different capsid serotypes determine distinct tissue tropisms in preclinical rodent models as well as in larger animal models such as dogs and primates. In experiments with rodent and primate models, AAV1, 6, and 9 have successfully transduced cardiac and skeletal muscle, while AAV8 is the capsid of choice for liver and eye transduction. To achieve efficient CNS transduction, AAV1, AAV2, AAV5, AAV8, AAV9, and six new primate genome-related latent AAV serotypes in rodent neonates have been used in different experimental paradigms.