体内作为新型神经治疗方法-猫眼课题宝

体内作为新型神经治疗方法

批准号：

7750565

负责人：

ANNE MESSER

金额：

$34.49万

依托单位：

WADSWORTH CENTER

依托单位国家：

美国

项目类别：

财政年份：

2006

资助国家：

美国

项目状态：

已结题

起止时间：

2006-01-15 至 2011-12-31

来源：

https://reporter.nih.gov/project-details/7750565

关键词：

Acquired Immunodeficiency Syndrome Affinity Alzheimer&apos s Disease Amino Acids Animals Antibodies Antibody Specificity Behavior Behavioral Binding Biological Assay Brain Brain region Cell Culture Techniques Cell Line Cell model Cells Characteristics Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Complex Corpus striatum structure DARPP 32 Data Dependovirus Disease Disease model Drosophila genus Engineering Epitopes Equine Infectious Anemia Virus Exons Functional disorder Gene Delivery Gene Transduction Agent Generations Genes Genetic Goals Huntington Disease Immunoglobulin Fragments In Situ Individual Investigation Knock-in Mouse Length Libraries Long-Term Effects Malignant Neoplasms Mammalian Cell Modeling Molecular Genetics Mus N-terminal Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neurologic Mutants Mice Neurons Nuclear Parkinson Disease Pathogenesis Primate Lentiviruses Prion Diseases Property Proteins Protocols documentation Rabies Reagent Recombinants Research Design Safety Screening procedure Slice Specificity Staging Subfamily lentivirinae Surface System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Viral Work Yeasts adeno-associated viral vector aged antibody engineering congenic disease phenotype drug discovery experience human Huntingtin protein human disease in vivo innovation mouse model mutant novel novel strategies polyglutamine protein misfolding protein protein interaction research study small molecule tool viral gene delivery

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中文摘要

翻译

本建议的目标是优化工程化的细胞内抗体（体内抗体）

英文摘要

The goal of this proposal is to optimize engineered intracellular antibodies (intrabodies) as novel clinical reagents and drug discovery tools for the treatment of Huntington's Disease (HD), with broad, long-term relevance to other neurodegenerative disorders caused by misfolded proteins. Intrabodies use the target specificity of antibodies to form complexes with intracellular proteins, and are already in clinical trials for treatment of cancers and AIDS. The research design starts with in vivo testing with a single-chain Fv anti-huntingtin (htt) intrabody (scFv C4) that has shown significant rescue of HD phenotypes in cell lines, organotypic slice cultures and a Drosophila HD model; plus a newer single domain intrabody (VL 12.3)that shows even stronger anti-htt aggregation properties in situ. Delivery of the intrabody genes will utilize a non-primate lentivirus, Equine Infectious Anemia Virus (EIAV), with either a VSVG or Rabies-g envelope, as one gene therapy vector, with some experiments to compare with delivery using AAV vectors provided by a collaborator. Quantitative assays of abnormal nuclear htt accumulation and aggregation, DARPP- 32 levels, and open field activity behavior will be used to assess the efficacy of the intrabodies delivered to the brains of Exon 1 transgenic (R6/1) and Hdh knock-in (Q111) mouse models on the same inbred genetic background. Simultaneously, screening and testing of a small pool of newer intrabodies will be done using anti-aggregation, protection, and toxicity assays in neuronal cell lines. The most successful of the new intrabodies will then be tested as above. If correction is incomplete with individual intrabodies, combination therapies will be tested in cells and in vivo. At the end of these studies, we will have established the optimal characteristics of intrabodies for eventual HD therapeutics and further drug discovery. These approaches should also be generally applicable for other neurodegenerative diseases that result from abnormal protein folding and accumulation, including Alzheimer's, Parkinson's, and prion diseases.

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