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

这一小型企业创新研究(SBIR)第二阶段项目的更广泛影响/商业潜力将是通过能够实现基因疗法的临床翻译的新技术来加强美国和全球的医疗保健。生物技术中尚未得到满足的主要需求之一是一种交付技术，该技术使基因疗法能够到达人体内所需的器官，而不会引发免疫反应。最近的进展揭开了许多潜在的遗传病治疗方法的面纱，但由于缺乏给药技术，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，并将其应用于一种罕见疾病的商业用途。该项目为尿素循环障碍患者提供了一种基因替代疗法，目前这些患者正在使用药物和饮食的组合进行治疗，但效果有限。他们的养生法每天需要多达40粒药片，并结合令人难以置信的严格的饮食控制，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损伤和新生儿死亡率高。照顾者面临着监测饮食、补充剂和药物的护理负担。一种提供真正疾病纠正的基因替代疗法将对患者和照顾者产生革命性影响。拟议中的项目将导致开发一种基因替代疗法，这种疗法可以安全地反复给患有尿素循环障碍的罕见疾病的患者使用。这些患者缺乏尿素循环中的一种酶，这种酶不能通过外源传递。另一种治疗方法是以核酸的形式(如信使核糖核酸)传递指令，让体内细胞制造缺失的酶。商业证明的方法--脂质纳米粒和病毒载体--由于毒性、免疫原性和剂量挑战而在这一适应症中失败。在这个项目中开发的平台提供了一种使用非病毒、聚合物-脂质杂化配方来克服这些限制的方法。该项目的范围包括对I型尿素循环障碍瓜氨酸血症啮齿动物模型的药理学和毒理学研究，这将产生一个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具有强大安全性的疾病纠正(降低血氨水平)的临床前演示。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.