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

补充提案 聚焦超声辅助脑内非病毒基因编辑系统的评价 摘要 大脑的有效非病毒基因编辑可能有助于解决一些顽固的神经退行性疾病。 紊乱与病毒基因编辑相比，它更具可翻译性，因为它应该具有更好的可管理性。 毒性和免疫原性。许多基因编辑应用程序可能需要多次施用，如果存在一个或多个基因编辑应用程序的话。 组织的高周转率。病毒基因编辑系统将是不合适的，因为担心 免疫原性大脑非病毒基因编辑的主要障碍是BBB。我们以前开创了 使用聚焦超声（FUS）技术实现非侵入性、脑特异性的治疗递送， 有效载荷包括小分子、蛋白质和腺相关病毒（AAV）。本补充提案 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已经在除脑以外的组织中显示出有希望的编辑效率。所述FUS 将在哥伦比亚对Ai9小鼠进行递送，并将脑组织送往JAX进行独立基因测序。 编辑分析最终实验设计将与PI协商确定。这种不偏 比较研究将确定非病毒大脑基因编辑在大脑辅助中的可能性和局限性 的FUS。

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.