Optimal volume and dose of AAV9-mCherry in stereotaxic targeting of putamen in C57BL/6 mice

ASGCT 2025 -- It is estimated that approximately 3% of the population is affected with some form of monogenic neurological disorder. Adeno-associated virus (AAV) gene therapy has the potential to treat these central nervous system indications; however, delivering the viral vector carrying the correct genetic information to the specific neural tissue is a significantly challenging process. Systemic administration of the viral vector results in a greater dose requirement to achieve clinically relevant levels due to difficulty navigating the blood-brain barrier. This in turn increases exposure in non-target tissues and the risk of immunotoxicity associated with a broader biodistribution and can result in increased off-target expression. A direct, stereotaxic administration of AAV gene therapy can safely and effectively deliver genetic payload into defined structures in the brain, alleviating concerns associated with systemic administration. This requires a lower vector dose for clinically relevant transgene expression, posing a lower risk of full immune response and limiting unwanted expression in non-target tissues.