Preclinical study demonstrates superior brain transduction and reduced off-target accumulation for CNSRCV300 in mice, highlighting safer vector design for central nervous system gene therapy.
The blood-brain barrier (BBB) severely restricts the efficacy of systemic adeno-associated virus (AAV) gene therapy for central nervous system (CNS) disorders. Here, we systematically characterized the in vivo tissue distribution and expression patterns of three BBB-crossing AAV capsids (PHP.eB, CNSRCV300, BI-hTFR1) after intravenous delivery in mice, using the ubiquitous CAG promoter and neuron-specific hSyn promoter to drive reporter expression. Compared with conventional AAV9, PHP.eB and CNSRCV300 exhibited enhanced BBB penetration and brain transduction, with predominant neuronal tropism. Relative to the CAG promoter, hSyn slightly attenuated cerebral transgene expression and markedly diminished peripheral off-target expression. Nevertheless, immunofluorescence, qPCR and Western blot assays verified persistent AAV retention in peripheral tissues including the liver, indicating underlying safety hazards. Notably, CNSRCV300 achieved robust CNS transduction with minimal peripheral accumulation, conferring superior safety profiles and promising clinical potential. Collectively, AAV in vivo targeting is co-regulated by capsid variants and promoter characteristics. Neuronal-specific promoters efficiently mitigate peripheral off-target transgene expression but fail to eliminate residual peripheral viral deposition, a critical safety concern for systemic AAV therapy. This study provides systematic experimental evidence for the rational screening and optimization of CNS-targeted AAV vectors.
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Zhao et al. (2026) studied this question.
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