Evaluation of nonviral gene editing systems in the brain assisted by focused ultrasound

补充建议书 聚焦超声辅助脑内非病毒基因编辑系统的评价 摘要 对大脑进行有效的非病毒基因编辑可能有助于解决一些顽固的神经元变性 精神错乱。与病毒基因编辑相比，它更具可译性，因为它应该更易于管理 毒性和免疫原性。许多基因编辑应用程序可能需要多次管理，如果 组织的高周转率。病毒基因编辑系统将不适合，因为担心 免疫原性。对大脑进行非病毒基因编辑的主要障碍是血脑屏障。我们以前是先驱 利用聚焦超声(FUS)技术实现非侵入性、脑部特异性的治疗性输送 有效载荷包括小分子、蛋白质和腺相关病毒(AAV)。本补充建议 旨在比较其他SCGE团队开发的非病毒基因编辑系统。预计这些 非病毒基因编辑系统在大脑以外的组织中显示出了良好的编辑效率。福斯 哥伦比亚大学将在Ai9小鼠身上进行分娩，并将脑组织送到JAX进行独立基因 正在编辑分析。最后的实验设计将在与私人投资促进机构协商后确定。这是不带偏见的 比较研究将确定在大脑辅助下进行非病毒脑基因编辑的可能性和局限性 由FUS提供。

Supplemental Proposal Evaluation of nonviral gene editing systems in the brain assisted by focused ultrasound Abstract Efficient nonviral gene editing of the brain may help tackle some of the intractable neuronal degenerative disorders. Compared with viral gene editing, it is more translatable since it should have more manageable toxicity and immunogenicity. Many gene editing applications may require multiple administrations if there is a high turnover of the tissue. Viral gene editing systems would be unsuitable because of concerns of immunogenicity. The major barrier to nonviral gene editing of the brain is the BBB. We previously pioneered the use of focused ultrasound (FUS) technology to achieve noninvasive, brain-specific delivery of therapeutic payloads including small molecules, proteins and adeno-associated virus (AAV). This Supplemental proposal aims to compare the nonviral gene editing systems developed by other SCGE teams. It is expected that these nonviral gene editing systems have shown promising editing efficiency in tissues other than the brain. The FUS delivery will be performed at Columbia on Ai9 mice and the brain tissues sent to JAX for independent gene editing analysis. The final experimental design will be established in consultation with the PIs. This unbiased comparative study will define the possibilities and limitations of nonviral brain gene editing in the brain assisted by FUS.