Chimeric AAV vector-mediated gene therapy holds potential for neurological diseases

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Scientists at the University of North Carolina at Chapel Hill have developed a chimeric AAV2g9 vector for efficient ‘neuronal’ gene transfer and limited systemic leakage. Application of AAV2g9 for targeted disruption of the schizophrenia risk gene MIR137 in CRISPR/Cas9 transgenic mice demonstrates its potential as a promising platform for treating Schizophrenia and other neurological disorders.

Gene therapy based on recombinant adeno-associated virus (AAV) vectors have advanced significantly over the past decade and recent developments in several phase 1 clinical trials proposes AAV vector as a promising approach to treat central nervous system (CNS) disorders. However, vector dose-related toxicity in off-target cells and organs remains a major challenge for CNS-targeted gene therapy, highlighting the importance of developing novel strategies to increase neurotropism and minimise off-target effects.

In the present study published in Molecular Therapy Nucleic Acids, the research team led by Prof. Aravind Asokan developed and characterized a novel chimeric AAV vector (AAV2g9) derived from AAV2 and AAV9. AAV2g9 preferentially transduced neurons over glia, while AAV9 vectors infected more glial cells. This neuronal tropism of AAV2g9 was attributed to its heparin binding characteristic. A comparison of the systemic leakage, biodistribution and gene expression profiles in peripheral organs resulting from two routes of administration in neonatal and adult rodents showed that, unlike AAV9, AAV2g9 displayed significantly reduced systemic leakage following CNS administration and resulted in lower sequestration and minimal transgene expression in peripheral organs.

Furthermore, a single intracranial injection of AAV2g9 vectors encoding two guide RNAs targeting the schizophrenia risk gene MIR137 (encoding MIR137) in CRISPR/Cas9 knockin mice resulted in brain-specific gene deletion with no detectable adverse events in the liver.

Thus, the study proposes AAV2g9 vector as a promising platform for treating neurological disorders through gene therapy, silencing or editing modalities. The neurotropic property of AAV2g9 makes it suitable for CNS gene transfer applications targeting neurons.

Source: CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector. Murlidharan G et al., Molecular Therapy Nucleic Acids July 2016. DOI