SBIR Phase II: Synthetic biology platform for production of stabilized high-value proteins

The broader impact of this Small Business Innovation Research (SBIR) Phase II project is to help patients living with diabetes. The disease accounts for 12% of deaths in the US and patients face major lifestyle changes. Most patients transition to insulin replacement therapy, which carries a complex dosing schedule that, if not followed closely, can leave patients in dangerous states of glucose dysregulation. More than 50 million diabetics currently use basal insulin analogs designed for longer activity than human insulin. The convenience and improved safety of these analogs has led to widespread adoption and a global market surpassing $10B. However, all current basal insulins require daily injections, a dosing burden that leads to poor treatment adherence, leaving patients vulnerable to dangerous fluctuations in blood glucose. The modified insulin described in this Phase II project is intended to provide the stability necessary to achieve once-weekly dosing. Relaxing the injection schedule should dramatically improve compliance and safety for patients; furthermore, the solution can be delivered at lower cost. The project uses a scalable in vivo protein production platform to produce long-acting insulin analogs for the diabetes market. The project utilizes the platform’s unique capability to site-specifically install non-standard amino acids into proteins, and to produce the modified proteins at scale. By replacing key bond-forming amino acids in insulin with non-standard amino acids that form stronger bonds, the modified insulins can achieve the stability necessary to support once-weekly dosing. The research objectives are to: produce sufficient quantities of variants of this insulin analog to support an experimental program, demonstrate improved stability of the variants over wild-type insulin in cell-based assays, and demonstrate sufficiently prolongated pharmacodynamics of the insulin analogs in an animal study to support once-weekly dosing. Potential outcomes include the first insulin analog capable of filling a major clinical and commercial need for affordable, safe insulin analogs with relaxed dosing schedules. Further, the work provides technical validation of a novel protein production platform. 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.