SBIR Phase II: Development of a safe gene editing system via CRISPR-Cas and Cas inhibitor co-delivery

SBIR II 期：通过 CRISPR-Cas 和 Cas 抑制剂共同传递开发安全基因编辑系统

• 批准号: 2136335
• 负责人: David Rabuka
• 金额: $ 100万
• 依托单位: ACRIGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2136335&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Development; safe

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be the development of a curative therapy for spinal muscular atrophy using a novel and proprietary precision gene editing technology. The proposed technology will increase the safety and efficacy of gene editing by optimizing the precision of editing to correct the disease. This technology can be used to improve and even cure patients of genetic disease.This Small Business Innovation Research (SBIR) Phase II project will develop and validate a curative therapy for spinal muscular atrophy (SMA) using a novel and proprietary CRISPR-Cas precision gene editing system. Manipulation of the human genome using CRISPR-Cas gene editors has been validated in early clinical trials to correct genetic diseases. However, application of this technology has been limited by the high degree of unintended 'off-target' editing events. This problem is particularly acute for in vivo therapies where the editing system will be delivered systemically or directly to the target organs, eliminating the ability to screen cells for unwanted editing outcomes. High precision gene editing technology must be developed to ensure the safety and efficacy of in vivo gene editing therapies. This project will develop an engineered anti-CRISPR (ErAcr) protein to eliminate unintended off-target editing. The ErAcr protein will be paired with a novel CRISPR-Cas nuclease and developed into a therapy for SMA The therapy will be packaged into an adeno-associated viral vector and tested for editing and SMA disease correction in patient-derived cells and in an SMA mouse model. Effective editing will lead to disease correction in both patient cells and mice with no observable off-target editing events.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个小企业创新研究（SBIR）第二阶段项目的更广泛的影响/商业潜力将是使用新颖和专有的精确基因编辑技术开发脊髓性肌萎缩症的治疗性疗法。这项技术将通过优化编辑的精确度来提高基因编辑的安全性和有效性，以纠正疾病。这项技术可用于改善甚至治愈遗传病患者。这个小企业创新研究（SBIR）二期项目将使用新型专有的CRISPR-Cas精确基因编辑系统开发和验证脊髓性肌萎缩症（SMA）的治愈性疗法。使用CRISPR-Cas基因编辑器操纵人类基因组已在早期临床试验中得到验证，以纠正遗传疾病。然而，该技术的应用受到高度非预期的“脱靶”编辑事件的限制。这个问题对于体内治疗特别严重，其中编辑系统将全身或直接递送到靶器官，消除了筛选细胞以获得不需要的编辑结果的能力。必须开发高精度的基因编辑技术，以确保体内基因编辑疗法的安全性和有效性。该项目将开发一种工程化的抗CRISPR（ErAcr）蛋白，以消除非预期的脱靶编辑。ErAcr蛋白将与一种新型CRISPR-Cas核酸酶配对，并开发成SMA疗法。该疗法将被包装到腺相关病毒载体中，并在患者来源的细胞和SMA小鼠模型中进行编辑和SMA疾病校正测试。有效的编辑将导致患者细胞和小鼠的疾病纠正，并且不会出现可观察到的脱靶编辑事件。该奖项反映了NSF的法定使命，并且通过使用基金会的知识价值和更广泛的影响力进行评估，被认为值得支持审查标准。