Intrabody Therapy in Drosophila for Huntington's Disease

果蝇体内治疗亨廷顿病

• 批准号: 7140440
• 负责人: WILLIAM J WOLFGANG
• 金额: $ 17.59万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-18 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140440
• 关键词: Drosophilidae; Huntington' s disease; antibody; genetic screening; genetically modified animals; immunopharmacology; immunosuppression; immunotherapy; laboratory mouse; nerve /myelin protein; neural degeneration

DESCRIPTION (provided by applicant): The overall goal of our work is to cure Huntington's Disease (HD). This proposal seeks to evaluate new intracellular antibodies (intrabodies) directed against the Huntingtin (htt) protein using an established Drosophila model for HD. Work in tissue culture cells and brain slice preparations has demonstrated that intrabodies can ameliorate pathology associated with expression of mutant forms of the htt. We have recently demonstrated that our prototypical anti-htt intrabody, C4 scFv, partially suppresses HD pathology in the functioning nervous system of Drosophila. The degree of suppression is quantifiable, allowing the rapid evaluation of new intrabodies for improved efficacy over our existing intrabody. Additionally, through unbiased functional genetic screens available in Drosophila, the cellular processes triggered by the intrabody/target interaction that result in disease correction can be elucidated. Identification of cellular pathways involved in intrabody-dependent correction of pathology will allow us to devise strategies to augment intrabody therapy as well as predict potential deleterious side effects. Finally, we will develop new models for testing intrabodies in flies. Currently, the intrabody and disease-causing htt transgene are co-expressed from early embryonic stages onward. In humans, therapy with intrabodies would likely commence in adults after the onset of diseases. Our new model will allow testing of intrabody efficacy at any time subsequent to the onset of disease. If successful this will provide validation of intrabodies as disease therapeutics and impetus to proceed to preclinical testing in vertebrate models of HD.

描述（由申请人提供）：我们工作的总体目标是治愈亨廷顿病（HD）。本研究旨在利用已建立的果蝇HD模型，评估针对亨廷顿蛋白（htt）的新的细胞内抗体（体内抗体）。在组织培养细胞和脑切片制备方面的工作已经证明，体内可以改善与htt突变形式表达相关的病理。我们最近已经证明，我们体内的原型抗htt， C4 scFv，部分抑制了果蝇功能神经系统的HD病理。抑制程度是可量化的，允许快速评估新的体内药物，以提高现有体内药物的疗效。此外，通过在果蝇中可用的无偏见功能遗传筛选，可以阐明由体内/靶标相互作用引发的导致疾病纠正的细胞过程。识别参与体内依赖病理纠正的细胞通路将使我们能够设计出增加体内治疗的策略，并预测潜在的有害副作用。最后，我们将开发新的模型来测试体内的苍蝇。目前，从胚胎早期开始，体内和致病的htt转基因就共同表达。在人类中，体内治疗可能在成人发病后开始。我们的新模型将允许在疾病发作后的任何时间测试体内疗效。如果成功，这将验证体内作为疾病治疗方法的有效性，并推动进行HD脊椎动物模型的临床前试验。