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

这个SBIR第二阶段项目旨在开发一种新的工程微生物组，作为一种名为Netherton综合征的罕见皮肤病的潜在治疗方法。Netherton综合征(NS)是一种罕见的严重皮肤病，死亡率高，治疗方案少。这项提议旨在开发一种治疗这种疾病的新方法，一种基于微生物的Lekti蛋白输送系统，Lekti是导致NS症状的缺失蛋白。在该项目结束时，候选的活生物治疗产品候选(分泌LETKI的表皮葡萄球菌菌株)将被提名，该公司将拥有足够的数据，用于进行正式的临床前研究和随后的人体测试。这种拟议的产品将有可能解决美国数以千计的患者的问题，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新的治疗候选药物，它由一种能向皮肤分泌Lekti蛋白的表皮葡萄球菌工程菌株组成，用于治疗Netherton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物淋巴上皮型Kazal相关抑制物(Lekti)的SPINK5基因突变引起的，该抑制物包含15个丝氨酸蛋白酶抑制域。这个第二阶段项目的目标是展示一种治疗NS的概念验证疗法：一种将LETKI的离散结构域传递到皮肤的工程共生微生物。拟议的第二阶段研究计划将为提名潜在的活性生物治疗产品(LBP)候选药物建立关键标准，该候选药物由分泌Lekti的表皮葡萄球菌组成。这项研究将在LBP的临床前开发中执行关键活动：确定最佳的lekti序列；开发用于检测表皮葡萄球菌工程菌株分泌的lekti的分析方法；以及开发用于在人体体外模型中测量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。

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.