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氏病（HD）。该提案旨在使用已建立的果蝇HD模型评估针对亨廷顿蛋白（htt）的新细胞内抗体（胞内抗体）。在组织培养细胞和脑切片制备中的工作已经证明胞内抗体可以改善与htt突变形式表达相关的病理学。我们最近已经证明，我们的原型抗htt胞内抗体，C4 scFv，部分抑制HD病理在果蝇的功能神经系统。抑制的程度是可量化的，允许快速评估新的胞内抗体相对于我们现有的胞内抗体的改善的功效。此外，通过果蝇中可用的无偏功能遗传筛选，可以阐明由胞内抗体/靶相互作用触发的导致疾病纠正的细胞过程。识别细胞内依赖性病理学校正中涉及的细胞途径将使我们能够设计策略来增强内体治疗以及预测潜在的有害副作用。最后，我们将开发新的模型来测试苍蝇的胞内抗体。目前，胞内抗体和致病htt转基因从早期胚胎阶段开始共表达。在人类中，使用胞内抗体的治疗可能在疾病发作后在成人中开始。我们的新模型将允许在疾病发作后的任何时间测试体内效力。如果成功，这将提供胞内抗体作为疾病治疗剂的验证，并推动在HD的脊椎动物模型中进行临床前测试。