STTR Phase I: Development of a novel system to manufacture therapies inside the human body

这一小型企业技术转让(STTR)第一阶段项目的更广泛影响是，通过开发一种系统，直接在患者身上合成急需的药物疗法，改善药物输送。这一进展如果成功，将减少复杂和昂贵的制造需要，消除对冷藏药物运输和储存的依赖，并消除重复注射的需要。这种系统的开发将适用于人类健康和疾病的不同应用，将抵抗流行病或自然灾害造成的供应链中断，并将导致向全球不同患者群体公平地提供药物。拟议的项目旨在开发一种能够支持生物药物直接在体内传递的动态生命药物。在过去的十年里，人们已经进行了许多尝试，以使用工程细菌和病毒作为活药物来安全和高效地将生物制剂输送给人类。目前的系统充满了问题，主要源于这些载体的免疫原性。这一关键的技术和创新差距--在体内长期安全地直接生产生物制品--可以通过对无毒生物共生体进行基因工程来表达感兴趣的蛋白质来实现。在这项研究中，血液共生体将被基因工程改造为表达β-葡萄糖脑苷酶或胰岛素，目标是产生分别治疗高谢病和糖尿病的活药物。工程化合物的分泌、活性和持久性将在体外和体内进行评估。这种治疗方法的安全性和有效性将在临床前模型中进行评估。这一奖项反映了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 of this Small Business Technology Transfer (STTR) Phase I project is to improve drug delivery by developing a system to synthesize much needed drug therapies directly in patients. This advancement, if successful, would reduce the need for complex and expensive manufacturing, eliminate the reliance on refrigerated drug shipment and storage, and remove need for repeated injections. Development of such a system would be adaptable for different applications across human health and disease, would be resistant to supply chain disruptions caused by pandemics or natural disasters, and would result in the equitable delivery of medications to diverse patient populations across the globe. The proposed project seeks to develop a dynamic living medicine capable of supporting the delivery of biological drugs directly in vivo. Over the last decade, many attempts have been made to deliver biologics safely and efficiently to humans using engineered bacteria and viruses as living medicines. The current system is fraught with problems, mostly stemming from the immunogenicity of these vectors. This critical technological and innovation gap - the manufacture biologics directly in vivo safely for extended periods of time - may be achieved through the genetic engineering of avirulent organism symbionts to express proteins of interest. In this study, blood symbionts will be genetically engineered to expresses either β-glucocerebrosidase or insulin, with the goal of generating living medicines to treat Gaucher’s disease and diabetes, respectively. The secretion, activity, and durability of the engineered compounds will be assessed in vitro and in vivo. The safety and efficacy of this therapeutic approach will be assessed in pre-clinical models.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.