bioRxivNeurosciencePreprint
Novel Engineered AAV Variants Demonstrate Superior Blood-Brain Barrier Penetration and Safety in Non-Human Primates
Zhenhua WangiD, Hao LiiD, Xianggang Xu, Z. P Sun, Rui HeiD, Linlin Zhang, Mengmeng YuiD, Shengwen Wang, Can Hu, Lei Liu, Lele Ren, Yanling Xu, Tongqian Xiao, Daoyuan Li, Bo Sun, Youguang Luo, Zhenming An
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.
- organism: non-human primate
- research focus: drug response / drug discovery
- approach: experimental assay
- Citations
- 1
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