SBIR Phase II: Re-engineered skin bacteria as a novel topical drug delivery system

该SBIR II期项目旨在开发一种新型工程微生物组，作为一种名为内瑟顿综合征的罕见皮肤病的潜在治疗方法。内瑟顿综合征（NS）是一种罕见的严重皮肤病，死亡率高，治疗选择少。该提案旨在为这种疾病开发一种新的治疗方法，一种基于微生物的LEKTI蛋白递送系统，LEKTI是负责NS症状的缺失蛋白。在该项目结束时，候选活生物素产物候选物（S. epidermidis）的临床试验，公司将有足够的数据进行正式的临床前研究和后续的人体试验。这一拟议产品将有可能解决美国数千名患者的问题，这种基于微生物的技术的更广泛的原理证明为治疗数百万患有皮肤病的患者提供了巨大的潜力。该项目旨在开发一种由S.分泌LEKTI蛋白至皮肤的表皮细胞用于治疗内瑟顿综合征（NS）。NS是一种罕见但严重的常染色体隐性遗传病，影响皮肤，头发和免疫系统。NS是由编码丝氨酸蛋白酶抑制剂淋巴上皮Kazal型相关抑制剂（LEKTI）的SPINK 5基因中的突变引起的，该基因含有15个丝氨酸蛋白酶抑制结构域。这个第二阶段项目的目标是证明NS的概念验证治疗：一种工程化的微生物，将LETKI的离散域传递到皮肤。拟议的第二阶段研究计划将建立提名一个潜在的活生物制品（LBP）的候选人组成的LEKTI分泌S的关键标准。表皮本研究将在LBP的临床前开发中进行关键活动：确定LEKTI的最佳序列;开发用于检测从S.表皮葡萄球菌分泌的LEKTI的生物分布和吸附的分析方法。该奖项反映了NSF的法定使命，并被认为值得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来支持。

This SBIR Phase II project aims to develop a novel engineered microbiome as a potential therapeutic for a rare skin disease called Netherton syndrome. Netherton syndrome (NS) is a rare, severe skin disease with high mortality and few treatment options. This proposal aims to develop a new therapeutic for this disease, a microbe-based protein delivery system of LEKTI, the missing protein responsible for NS symptoms. At the end of this project, a candidate live biotherapeutic product candidate (LETKI-secreting strain of S. epidermidis) will be nominated and the Company will have sufficient data with which to proceed into formal preclinical studies and subsequent human testing. This proposed product will have the potential to address thousands of patients in the U.S., and the broader proof-of-principle of this microbe-based technology offers significant potential to treat millions of patients living with skin conditions. This offers significant advances in innovation in addition to broad commercial potential.This project aims to develop a novel therapeutic candidate composed of an engineered strain of S. epidermidis that secretes LEKTI protein to the skin for the treatment of Netherton syndrome (NS). NS is a rare but severe autosomal recessive disease that affects the skin, hair, and immune system. NS is caused by mutations in in the SPINK5 gene encoding the serine protease inhibitor lymphoepithelial Kazal-type related inhibitor (LEKTI), which contains 15 serine protease inhibitory domains. The goal of this Phase II project is to demonstrate a proof-of-concept therapeutic for NS: an engineered commensal microbe that delivers discrete domains of LETKI to the skin. The proposed Phase II research plan will establish critical criteria for nominating a potential live biotherapeutic product (LBP) candidate composed LEKTI-secreting S. epidermidis. This research will perform key activities in preclinical development of an LBP: identify an optimal sequence of LEKTI; develop analytical methods for detecting LEKTI secreted from an engineered strain of S. epidermidis; and develop analytical methods for measuring biodistribution and adsorption of LEKTI secreted by S. epidermidis in a human in vitro model.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.