SBIR Phase II: Formulation of a mRNA-Based Therapy for CTLN1 by Inverse Flash NanoPrecipitation

SBIR II 期：通过反向闪速纳米沉淀制定基于 mRNA 的 CTLN1 疗法

• 批准号: 2233286
• 负责人: Robert Pagels
• 金额: $ 100万
• 依托单位: Optimeos Life Sciences, Inc.
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2233286&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Formulation; mRNA

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be to enhance American and global healthcare through new technologies enabling clinical translation of gene therapies. One of the major unmet needs within biotechnology is a delivery technology that enables gene therapies to reach the desired organ within the body without raising an immune response. Recent advances have unlocked many potential treatments for genetic diseases, but their use in the clinic is hampered by a lack of delivery technologies. This project will validate a new non-viral platform for this purpose and apply it to commercial use in a rare disease indication. The project provides a gene replacement therapy for Urea Cycle Disorder patients, who are currently treated using a combination of drugs and diet that shows limited effectiveness. Their regimens require up to 40 pills per day in combination with incredibly strict dietary control to avoid consuming too much protein. Even still, elevated blood ammonia results in neurological damage and high neonatal mortality. Caregivers face significant burdens of care to monitor diet, supplements, and medications. A gene replacement therapy that provides true disease correction would be transformational for patients and caregivers. The proposed project will result in the development of a gene replacement therapy that can be safely and repeatedly dosed to patients suffering from the class of rare diseases known as Urea Cycle Disorders. These patients lack an enzyme of the urea cycle that cannot be delivered exogenously. An alternative therapeutic approach is to deliver instructions, in the form of nucleic acids such as mRNA, for cells in the body to make the missing enzyme. The commercially proven methods of doing this – lipid nanoparticles and viral vectors – fail in this indication due to toxicity, immunogenicity, and dosing challenges. The platform developed in this project provides a means to overcome these limitations using a non-viral, polymer-lipid hybrid formulation. The scope of the project includes both pharmacology and toxicology studies in rodent models of the Urea Cycle Disorder Citrullinemia Type I, that will produce a pre-clinical data package supporting further development. Successful project execution will include formulation optimization and pre-clinical demonstration of disease correction (reduced blood ammonia levels) with a strong safety profile.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/商业潜力将通过新技术增强美国和全球医疗保健，使基因疗法的临床翻译成为可能。生物技术中未满足的主要需求之一是一种递送技术，该技术使基因疗法能够到达体内所需的器官而不引起免疫反应。最近的进展已经为遗传疾病提供了许多潜在的治疗方法，但由于缺乏交付技术，它们在临床上的使用受到阻碍。该项目将为此目的验证一种新的非病毒平台，并将其应用于罕见疾病适应症的商业用途。该项目为尿素循环障碍患者提供了基因替代疗法，这些患者目前使用药物和饮食组合治疗，效果有限。他们的方案每天需要多达40片药丸，并结合非常严格的饮食控制，以避免摄入过多的蛋白质。即使如此，血氨升高也会导致神经系统损伤和新生儿死亡率高。护理人员面临着监测饮食、补充剂和药物的重大护理负担。提供真正的疾病矫正的基因替代疗法将对患者和护理人员产生变革性影响。拟议的项目将导致开发一种基因替代疗法，可以安全地重复给药于患有称为尿素循环障碍的罕见疾病的患者。这些患者缺乏尿素循环的酶，不能外源性输送。另一种治疗方法是以核酸（如mRNA）的形式向体内细胞发出指令，使其制造缺失的酶。由于毒性、免疫原性和剂量挑战，商业上证明的方法-脂质纳米颗粒和病毒载体-在这种适应症中失败。该项目中开发的平台提供了一种使用非病毒聚合物-脂质混合制剂克服这些限制的方法。该项目的范围包括在I型尿素循环障碍瓜氨酸血症啮齿动物模型中进行的药理学和毒理学研究，这将产生支持进一步开发的临床前数据包。成功的项目执行将包括配方优化和临床前疾病纠正示范（降低血氨水平），并具有很强的安全性。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。