AAV PHP.eB-CAG-Cre-GFP

Currently, the most promising viral vectors for delivering gene therapies in the brain are based on adeno-associated viruses (AAV). AAV vectors have been used clinically as components of approved gene therapies and are in a rapidly increasing number of trials for the treatment of central nervous system (CNS) diseases. Clinical use has shown that AAV vectors are safe, well tolerated, relatively low in immunogenicity, highly efficient in transduction, and able to transduce both dividing and quiescent cells in vivo. AAV exhibits cell type specificity determined by the different serotypes of viral capsid proteins reproducing them.

The Cre Recombination-Based AAV Targeted Evolution (CREATE) platform was used to generate variants of AAV9: AAV-PHP.B and enhanced AAV-PHP.eB, which penetrate the blood-brain barrier (BBB) ​​more efficiently than AAV9 after systemic delivery. They have improved CNS tropism, resulting in widespread transduction of neurons and glial cells throughout the mouse brain. Although these variants have a 40-fold higher transduction efficiency than AAV9, transduction levels may vary. Furthermore, the transduction capacity of AAV-PHP variants has been shown to be strain- and species-specific. In mice, the CNS tropism of AAV-PHP.B and AAV-PHP.eB is absent in certain inbred strains (e.g., BALB/cJ), and the ability of these viruses to cross the BBB depends on a single nucleotide variant in the Ly6a gene, which encodes the receptor for the AAV-PHP capsid.