AAV PHP.B-mCherry

Neurodegenerative diseases are a group of multisystem disorders that affect the central nervous system (CNS) and have limited treatment options. An important and challenging aspect of treating these diseases is effective targeted drug delivery. Viral vectors carrying therapeutic nucleic acid molecules must be delivered to the CNS to exert their therapeutic effects at the desired site. Delivery of viral vectors is part of molecular neurosurgery, whereby diseases are treated at the molecular level. Various disease-modifying therapies are in the (preclinical) phase for neurodegenerative diseases that use adeno-associated viruses (AAVs) as nucleic acid delivery vehicles.

When targeting the CNS via intravenous injection, an AAV capsid that is able to cross the blood-brain barrier (BBB) ​​is required. Various attempts have been made to improve the ability and efficiency of AAV to cross the BBB. A variant of AAV9, named AAV9-PhP.B, has been reported to enhance transduction of brain tissues such as the cortex 40-fold compared to its ancestor AAV9. PhP.B was constructed by inserting a 7-peptide at position I-588. The insertion site is located on the outside of the capsid, at the tip of a loop at the 3-fold symmetry axis, facilitating interaction with receptors on target cells. AAV9-PhP.B has been shown to be functional in mouse models. For example, gene therapy based on AAV9-PhP.B has been shown to reduce α-synuclein pathology in preclinical mouse models.