SBIR-STTR Award

The broader impact/commercial potential of this this Small Business Technology Transfer (STTR) Phase I project is the development of a novel messenger ribonucleic acid (mRNA)-based vaccine for COVID-19. The fastest-to-clinic vaccine for COVID-19 was mRNA-based; however, there are no mRNA-based vaccines on the market currently. This is, in part, because this class of vaccines is difficult to optimize and manufacture at a large scale. If clinical trials are successful, hundreds of millions of doses will be needed in the U.S. alone. This STTR project aims to pioneer a novel technique to manufacture mRNA-based vaccines initially for COVID-19. This technology is highly modular, allowing for the better understanding and optimization of this class of vaccines. Importantly, this new technique can be scaled to manufacture the doses needed both for the current COVID-19 pandemic and in the case of future outbreaks. The flexibility and scalability of this platform technology provide a durable competitive advantage. Following demonstration of preclinical efficacy, the company will work with an established pharmaceutical partner for testing and manufacturing. Capturing 5% of the U.S. COVID-19 vaccine market would bring an estimated $125 million in revenue. This is a beachhead market, and, once successful, the company will expand into other mRNA-based vaccine and therapeutic markets. This Small Business Technology Transfer (STTR) Phase I project aims to develop an mRNA-based nanoparticle vaccine for COVID-19 without the use of cationic materials. Current formulation methods require cationic lipids or polymers to form charge-based complexes with the anionic mRNA. Charge-based assembly limits the accessible nanoparticle surface chemistries, a feature crucial to directing which cell types will be transfected and the resulting immune response. Additionally, mRNA is only a minor component of the resulting formulations. The proposed formulation method decouples the mRNA encapsulation from the nanoparticle surface in a two-step process. The method does not require cationic materials, allowing for mRNA loadings up to 5-times higher than those achievable through other routes. However, mRNA transfection has not previously been demonstrated without the use of cationic materials. This will be achieved by completing three key milestones: (1) optimize mRNA encapsulation, (2) vary surface coatings to enhance dendritic cell uptake, and (3) demonstrate efficient cell transfection. A highly loaded nanoparticle formulation that can efficiently target and transfect dendritic cells is desired. Following the completion of this Phase I work, this formulation may be applied to a SARS-CoV-2 spike protein-coding mRNA to produce a COVID-19 vaccine. 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.

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.