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Novel Engineered AAV Variants Demonstrate Superior Blood-Brain Barrier Penetration and Safety in Non-Human Primates

Wang, Z.; Li, H.; Xu, X.; Sun, Z.; He, R.; Zhang, L.; Yu, M.; Wang, S.; Hu, C.; Liu, L.; Ren, L.; Xu, Y.; Xiao, T.; Li, D.; Sun, B.; Luo, Y.; An, Z.

2026-04-01 neuroscience
10.64898/2026.03.29.713052 bioRxiv
Show abstract

Systemic delivery of adeno-associated virus (AAV) for gene therapy of central nervous system (CNS) disorders is limited by inefficient blood-brain barrier (BBB) penetration and dose-limiting toxicity in peripheral organs, notably the liver and dorsal root ganglia (DRG)1-5. Here, we report the development of novel AAV variants via a proprietary capsid engineering platform (REACH). In non-human primates (NHPs), intravenous administration of lead variants resulted in transgene expression levels in the brain that were 600-2000 fold higher than AAV9 at the RNA level, concomitant with a 10-50 fold reduction in liver tropism and minimal off-target exposure in the heart and DRG. These engineered capsids achieve unprecedented, pan-CNS transduction with a markedly improved safety profile, representing a transformative platform for treating a broad spectrum of neurological diseases.

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