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

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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.