Innovative therapeutic strategies to support elimination of river blindness

摘要 盘尾丝虫病(河盲症)是由盘尾丝虫病引起的一种主要的(媒介传播的)被忽视的热带疾病。 并由世界卫生组织提议在2030年前消除传播。 目前，国家控制计划试图通过大规模给药伊维菌素(MDA)来实现EOT (Ivm)对≥5岁的个人，在较长的时期内。IVM具有微丝虫杀伤力(杀死微丝虫)。通过 2013年，自20世纪90年代初开始使用丙二醛与间隔性VM治疗以来，MF患病率仅降低了31%，S， 明确表示不会达到仅使用IVM的EOT。2018年批准的莫西菌素(MOX)用于 对12岁的≥患者的治疗是增强实现以下目标前景的一个重要里程碑 埃奥特。然而，由于MOX被认为主要是微丝杀伤性的(但见下文)，它可能不足以 到2030年在所有流行地区满足EOT。因此，开发新药和替代疗法 实现盘尾丝虫病EOT的养生法是当务之急。 我们建议开发新的药物和治疗方案，以促进人类持续消除 丝虫病，基于我们在以下方面的重大进展：a)识别含有大杀丝虫的丝虫病主打药物 活性及其假定的靶点；b)证明在体外，莫昔洛韦，一种候选的丙二醛药物和情绪化 (EMO)是一种临床开发中的大杀丝虫改变用途的药物，针对蠕虫的早期阶段 并因此可防止或减少成虫的形成(定义为 预防潜力)；以及c)将预防方案与IVM或 MOX已经表示，每两年或每季度一次的MOX MDA将大大有助于加快世卫组织的 与IVM相比，消除目标。 我们提出的目标建立在我们迄今取得的实质性进展的基础上，包括：i)理性 通过对已知HIV-天冬氨酸氨基转移酶的药物化学优化设计新的大丝虫杀菌药物候选药物 体外和体内对3种丝虫有活性的蛋白酶抑制剂(利托那韦、洛比那韦、奈非那韦)； 二)在体内同时评价MOX和EMO的预防潜力(根据#年的前景选择 人体的体外结果和已知的PK和PD曲线)，以及III)评估创新的联合治疗 体内方法(使用已建立的丝虫病动物模型)以及通过开展 数学建模以确定哪些干预措施将具有最大的加速潜力 并在非洲保护盘尾丝虫病埃奥特。 到该项目结束时，我们预计已经开发出针对以下目标的新型大丝虫杀灭药物候选药物 一种或多种天冬氨酸蛋白酶，用于高级临床前研究，并已确定开创性治疗 通过预防来养生，这将加强急需的补充工具来开发新的 促进人类盘尾丝虫病持续消除的综合治疗战略。

Abstract Onchocerciasis (river blindness) is a major (vector-borne) neglected tropical disease caused by Onchocerca volvulus and proposed by the World Health Organization for elimination of transmission (EOT) by 2030. Currently, national control programs attempt to achieve EOT with mass drug administration (MDA) of ivermectin (IVM) to individuals aged ≥5 years over prolonged periods. IVM is microfilaricidal (kills the microfilariae, mf). By 2013, only a 31% reduction in mf prevalence was achieved since MDA with IVM began in the early 1990’s, making it clear that EOT using IVM alone would not be reached. The 2018 approval of moxidectin (MOX) for treatment of individuals aged ≥12 years was a significant milestone in enhancing the prospects of achieving EOT. However, as MOX is deemed to be mainly microfilaricidal (but see below), it will likely not be sufficient to meet EOT by 2030 in all endemic areas. Therefore, the development of new drugs and alternative treatment regimens to achieve onchocerciasis EOT is a pressing need. We propose to develop novel drugs and treatment regimens for facilitating sustained elimination of human onchocerciasis, based on our significant progress on: a) identification of filarial hit drugs with macrofilaricidal activity and their putative targets; b) demonstration that in vitro, MOX, a candidate MDA drug and emodepside (EMO), a macrofilaricidal repurposed drug under clinical development, target the early stages of worm development and could consequently prevent or reduce the establishment of adult worms (defined as having prophylactic potential); and c) transmission dynamics modelling incorporating prophylactic regimens with IVM or MOX that has already indicated that bi-annual or quarterly MOX MDA would greatly help accelerate WHO’s elimination goals compared to IVM. Our proposed aims build on the substantial progress we have thus far made and comprise: i) rationally designing novel macrofilaricidal drug candidates via medicinal chemistry optimization of known HIV-aspartic protease inhibitors (ritonavir, lopinavir, nelfinavir) that are active against 3 filarial species in vitro and in vivo; ii) evaluating in parallel, in vivo, the prophylactic potential of MOX and EMO (selected based on promising in vitro results and known PK and PD profiles in humans), and iii) evaluating innovative combination treatment approaches in vivo (using well-established filariasis animal models) as well as in silico by undertaking mathematical modelling to identify which suites of interventions would have the greatest potential to accelerate and protect onchocerciasis EOT in Africa. By the end of the project, we anticipate to have developed novel macrofilaricidal drug candidates which target one or more aspartic proteases for advanced preclinical studies and to have identified pioneering treatment regimens through prophylaxis that will augment the critically needed complementary tools for developing new integrated therapeutic strategies for facilitating sustained elimination of human onchocerciasis.