Oncolytic virus targeting Schistosomes

针对血吸虫的溶瘤病毒

• 批准号: 10372084
• 负责人: BRUCE D FREEDMAN
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372084
• 关键词: Adolescent; Adult; Affect; Aftercare; Animal Model; Animal Testing; Biotechnology; Cancerous; Cell Proliferation; Cells; Clinical; Dangerousness; Deposition; Developing Countries; Development; Disease; Drug usage; European; Family; Female; Future; Goals; Helminths; High Prevalence; Human; Immune; Immune response; Immunocompetent; Immunodeficient Mouse; In Vitro; Infection; Injections; Investigation; Label; Lead; Life; Lytic; Malignant Neoplasms; Mammalian Cell; Mammals; Measures; Mediating; Monitor; Morbidity - disease rate; Morphology; Mus; Myxoma virus; Nature; Oncolytic; Oncolytic viruses; Oryctolagus cuniculus; Parasites; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Platyhelminths; Population; Poxviridae; Praziquantel; Production; Proliferating; Property; Reagent; Recombinants; Reproduction; Resistance; Risk; Safety; Schistosoma; Schistosoma mansoni; Schistosomiasis; Systemic disease; Testing; Therapeutic; Time; Tissues; Translating; Vaccines; Viral; Virus; Virus Diseases; Work; cancer cell; cancer therapy; cancer type; cell motility; cell transformation; co-infection; confocal imaging; disease transmission; egg; experimental study; fitness; high risk; in vivo; infection rate; innovation; male; member; microscopic imaging; mortality; neglected tropical diseases; new technology; new therapeutic target; novel; pathogenic virus; preclinical study; red fluorescent protein; response; socioeconomics; tumor; waterborne

Project summary: Schistosomiasis, a neglected tropical disease affects hundreds of millions of people worldwide and is associated with significant morbidity and mortality and imposes a high socioeconomic burden on many affected developing countries. Schistosomiasis is caused by water-borne parasitic trematodes of the genus Schistosoma, which can survive inside human hosts for decades. Disease pathology results from deposition of schistosome eggs in host tissues, which evokes an immunopathological response from the host. Recent work shows that oncolytic viruses with limited host range in mammals can eliminate cancer cells without harming the human host and these viruses are being actively investigated for potential clinical use. We recently performed preliminary studies showing that one of these oncolytic viruses is capable of infecting schistosomes and replicating within the parasites. Thus, exposure of Schistosoma mansoni to the virus in vitro results in 100% infection of worms, resulting in tegumental disruption, damage to other worm tissues, and parasite lethality. Unlike praziquantel, the current drug used to treat and control schistosomiasis, this oncolytic virus impacts all intramammalian parasite stage including schistosomula, juvenile, and adult schistosomes. This innovative exploratory proposal will confirm and extend these preliminary studies with the goals of determining the dynamics of infection and whether this oncolytic virus can be used to infect and potentially kill schistosomes in vivo without harming the host. Specifically, we will Aim 1: Determine the effects of oncolytic virus on the different life stages of schistosomes in vitro and Aim 2: Determine the effects of oncolytic virus on schistosomes within the mammalian host. We have excellent interdisciplinary collaborators to carry this project successfully. Accomplishment of these aims will serve as proof of concept and set the stage for more extensive refinement and testing in future work using animal models of infection and co-infection to understand the underlying parasite pathways and target the pathway hijacked by the virus, perhaps leading to new therapeutic targets. These studies will provide a platform to potentially use this oncolytic virus as a “schisto-lytic” agent due to its extremely narrow host range and could provide an effective safe schistosomiasis therapeutic. The approach will readily translate into groundbreaking new technology for treatment and control of schistosomiasis.

项目概要：血吸虫病，一种被忽视的热带疾病，影响数亿人 在世界范围内，与显著的发病率和死亡率相关，并造成很高的社会经济负担 许多受影响的发展中国家。血吸虫病是由水传播的寄生吸虫引起的， 血吸虫属，它可以在人类宿主体内存活数十年。疾病病理结果来自 寄生虫卵在宿主组织中的沉积，引起宿主的免疫病理学反应。 最近的工作表明，在哺乳动物中宿主范围有限的溶瘤病毒可以消灭癌细胞 而不伤害人类宿主，并且正在积极研究这些病毒的潜在临床用途。我们 最近进行的初步研究表明，这些溶瘤病毒之一能够感染 在寄生虫体内复制。因此，曼氏血吸虫在体外暴露于病毒 导致蠕虫100%感染，导致表皮破裂，损害其他蠕虫组织， 寄生虫致死率与目前用于治疗和控制血吸虫病的药物吡喹酮不同， 病毒影响所有哺乳动物体内寄生虫阶段，包括童虫、幼虫和成虫。 这一创新的探索性建议将确认和扩展这些初步研究，其目标是： 确定感染的动力学以及这种溶瘤病毒是否可用于感染和潜在地杀死 在不伤害宿主的情况下在体内寄生虫。具体而言，我们将目标1：确定溶瘤药物的作用。 目的2：确定溶瘤病毒对体外不同生命阶段的肿瘤小体的影响 病毒在哺乳动物宿主内的染色体上。我们拥有优秀的跨学科合作者， 把这个项目做好。这些目标的实现将作为概念的证明，并为 在未来的工作中，使用感染和合并感染的动物模型进行更广泛的改进和测试， 了解潜在的寄生虫途径，并瞄准被病毒劫持的途径，也许会导致 新的治疗靶点。这些研究将提供一个平台，有可能使用这种溶瘤病毒作为治疗药物。 “溶血”剂由于其极窄的宿主范围，可提供一种有效安全的血吸虫病 有治疗作用的这种方法将很容易转化为突破性的新技术，用于治疗和控制 血吸虫病