AAV PHP.eB-Syn-Cre

Targeting the central nervous system (CNS) using adeno-associated viruses (AAVs) has revolutionized gene therapy for neurological diseases. However, AAV vectors still face significant challenges in achieving broad and effective CNS biodistribution and transduction. Despite current clinical use, AAV9-mediated gene delivery requires high viral loads to achieve relatively limited transduction throughout the CNS. Recently developed Cre-dependent in vivo platforms for selection of targeted AAV capsids have led to the discovery of new engineered AAV9-derived variants, AAV.PHP.eB and AAV.PHP.B. Both constructs significantly improved viral blood-brain barrier (BBB) ​​penetration when delivered peripherally in mice. Considerable evidence, primarily AAV9, suggests that AAV can more effectively penetrate the entire CNS when delivered into the cerebrospinal fluid (CSF). Intrathecal administration of AAV9 improves CNS targeting in rodents and non-human primates (NHPs). Direct comparison of intravascular and intrathecal AAV.PHP.B injection systems revealed that injection into the cisterna pulvinar (CM) of NHPs had superior transduction properties compared to multiple intravascular injection routes. Intrathecal AAV.PHP.eB successfully achieved widespread transduction throughout the neuraxis, using a simplified ICM injection paradigm that can be used in aged rats with relatively low viral titers and minimal risk of adverse effects to subjects. Compared to AAV9, the AAV.PHP.eB vector has relative utility in developing gene therapies for rat models of neurodegenerative diseases and has the potential to provide more effective clinical treatments.