SBIR Phase I: Novel drug delivery system using engineered exosomes

小企业创新研究(SBIR)第一阶段项目的更广泛影响/商业潜力需要开发一种新的药物输送平台，将药物输送到难以获得药物的靶点。针对炎症的药物以一种新的方式被包裹起来，用于治疗牛皮癣、狼疮、类风湿性关节炎等慢性炎症性疾病。生物疗法仍然是自身免疫性疾病的标准疗法，但由于自身抗体的产生，患者可能会出现免疫系统问题。该项目通过一种新的封装技术来应对这一挑战，该技术将生物疗法提供给难以到达的炎症部位。这项技术可能是有利的，因为它减少了免疫抑制和抗药物抗体的产生。该项目将改善患者的治疗结果，减少治疗，降低成本。这个小型企业创新研究(SBIR)第一阶段项目将测试一项概念验证，该概念验证需要证明基于外显子的生物制剂递送载体将潜在地抑制不适当的TLR驱动的炎症。包括银屑病、类风湿性关节炎和狼疮在内的自身免疫性疾病的诱发与由内体TLRs介导的炎症信号通路驱动的慢性炎症密切相关。我们的目标是开发一种基于外体的治疗方法，可以抑制难于获得的TLR7内体驱动的炎症。为了测试这一概念，我们的计划涉及对人类细胞系进行基因改造，以生产含有抗TLR7抗体的工程化外体，以抑制内体TLR7驱动的炎症。我们将开发一种药物包埋平台，在该平台中，工程化外切体携带抗TLR7抗体与称为Tetraspanin的外切体跨膜蛋白融合。该复合体向位于内膜内表面的TLR7靶点传递抗体有效载荷。这种抗TLR7抗体将结合到TLR7单体的二聚体界面上，从而阻断TLR7受体的二聚化，进而阻断促炎信号。这项工作很重要，因为阻断TLR7受体的激活(位于信号级联的上游)可能会减少免疫抑制，并导致比目前更广泛的抗肿瘤坏死因子疗法更好的结果，因为它们的作用部位在信号通路轴的下游。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。

he broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase 1 project entails developing an novel drug delivery platform to deliver drug into poorly accessible druggable targets. Drugs targeting inflammation are encapsulated in an new way for treatment of chronic inflammatory diseases such as psoriasis, lupus, rheumatoid arthritis. Biological therapies remain the standard for autoimmune diseases, but patients can have immune system problems due to the production of autoantibodies. This project addresses this challenge with a novel encapsulation technology that delivers biological therapies to hard-to-reach inflammation sites. This technology could be advantageous because it reduces immunosuppression and anti-drug antibodies production. This project will improve patient treatment outcomes and reduce treatment reduce cost. This Small Business Innovation Research (SBIR) Phase 1 project will test a proof-of-concept that entails demonstrating that an exosome-based delivery vehicle for biologics will potentially inhibit inappropriate TLR-driven inflammation. Induction of autoimmune diseases including psoriasis, rheumatoid arthritis and lupus strongly correlate with chronic inflammation driven by inflammatory signaling pathways mediated by endosomal TLRs. Our goal is to develop an exosome-based therapy that can inhibit poorly accessible endosomal TLR7-driven inflammation. To test this concept, our plan involves genetically modifying human cell lines to produce engineered exosomes that contain anti-TLR7 antibody to inhibit endosomal TLR7-driven inflammation. We will develop a drug encapsulation platform in which engineered exosomes bear an anti-TLR7 antibody fused with an exosome transmembrane protein called tetraspanin. This complex delivers an antibody payload to TLR7 targets located in on endosomal membrane inner surface. This anti-TLR7 antibody will bind to dimer-interfaces of TLR7 monomer and thereby block TLR7 receptor dimerization, which in turn blocks proinflammatory signaling. This work is important because blocking TLR7 receptor activation, which is situated upstream in the signaling cascade, will presumably diminish immunosuppression and lead to a better outcome that current anti-TNF therapies that are more broad spectrum because their site of action is downstream in a signaling pathway axis.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.