Systemic delivery of adeno-associated viral (AAV) vectors is a promising approach for brain gene therapy, particularly in combination with emerging techniques such as focused ultrasound (FUS), which can transiently and noninvasively open the blood-brain barrier to facilitate delivery of AAVs to the brain. However, off-target vector accumulation, particularly in the liver, remains a significant safety concern. To address this, we introduced a mutation into variable region 1 of the AAV9 capsid (G266A) and assessed its effect on liver and brain transduction, testing both direct intraparenchymal injection and intravenous injection with FUS. Interestingly, we found that G266A mutation strongly decreased liver transduction while having only a modest effect on transduction of the brain and other tissues. We also found that the G266A mutation had minimal impact on cell attachment and uptake but strongly decreased binding of the capsid to both human and mouse AAV receptor (AAVR), which likely explains the decrease in liver transduction. Overall, our findings suggest that the G266A mutation and modification of AAVR binding could be a useful strategy to mitigate liver toxicity associated with systemic brain gene therapy.
Nelson et al. (Sun,) studied this question.