Intrabody Therapy in Drosophila for Huntington's Disease

果蝇体内治疗亨廷顿病

• 批准号: 6967006
• 负责人: WILLIAM J WOLFGANG
• 金额: $ 20.42万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967006
• 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舞蹈病（HD）。该提案旨在使用已建立的 HD 果蝇模型来评估针对亨廷顿蛋白 (htt) 蛋白的新细胞内抗体（胞内抗体）。组织培养细胞和脑切片制备工作表明，胞内抗体可以改善与 htt 突变形式表达相关的病理学。我们最近证明，我们的原型抗 htt 体内 C4 scFv 可以部分抑制果蝇功能神经系统中的 HD 病理。抑制程度是可量化的，可以快速评估新的体内，以提高现有体内的功效。此外，通过果蝇中可用的无偏见功能遗传筛选，可以阐明由体内/靶标相互作用触发的导致疾病纠正的细胞过程。识别参与体内依赖性病理校正的细胞途径将使我们能够设计出增强体内治疗并预测潜在有害副作用的策略。最后，我们将开发用于测试果蝇体内的新模型。目前，体内和致病 htt 转基因从早期胚胎阶段开始共表达。在人类中，体内治疗可能会在成人疾病发作后开始。我们的新模型将允许在疾病发作后的任何时间测试体内功效。如果成功，这将验证体内作为疾病治疗方法的有效性，并推动在 HD 脊椎动物模型中进行临床前测试。