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

这个小企业创新研究（SBIR）二期项目的更广泛影响是帮助糖尿病患者。该疾病占美国死亡人数的12%，患者面临重大的生活方式改变。大多数患者改用胰岛素替代疗法，这种疗法有一个复杂的给药计划，如果不严格遵守，可能会使患者处于血糖失调的危险状态。目前有超过5000万的糖尿病患者使用基础胰岛素类似物，其设计的活性比人用胰岛素更长。这些类似物的便利性和安全性得到了广泛采用，全球市场规模超过100亿美元。然而，目前所有的基础胰岛素都需要每天注射，这是一个剂量负担，导致治疗依从性差，使患者容易受到血糖危险波动的影响。在这个II期项目中描述的改良胰岛素旨在提供实现每周一次给药所需的稳定性。放宽注射时间表将显著提高患者的依从性和安全性；此外，该解决方案可以以更低的成本交付。该项目使用可扩展的体内蛋白质生产平台为糖尿病市场生产长效胰岛素类似物。该项目利用该平台的独特能力，将非标准氨基酸定位到蛋白质中，并大规模生产修饰蛋白质。通过将胰岛素中形成键的关键氨基酸替换为形成更强键的非标准氨基酸，改进后的胰岛素可以达到支持每周一次给药所必需的稳定性。研究目标是：生产足够数量的胰岛素类似物的变体以支持实验计划，在细胞基础试验中证明变体比野生型胰岛素的稳定性更好，并在动物研究中证明胰岛素类似物的药效学足够延长，以支持每周一次的剂量。潜在的结果包括第一种胰岛素类似物，能够满足主要的临床和商业需求，负担得起的，安全的胰岛素类似物，宽松的剂量计划。此外，这项工作为一种新的蛋白质生产平台提供了技术验证。该奖项反映了美国国家科学基金会的法定使命，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。

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.