Grant: $25,460 - National Institutes of Health - Jul. 20, 2009
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Award Description: 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
Project Description: Julie McLear Friot, Ph.D,. Assistant Professor of Biology at Utica College; Utica, NY spent 8 weeks doing research on Huntington’s Disease therapeutics, and training and supervising an undergraduate, Maggie Wright, also from Utica College. Julie’s personal development goals were completed -- she learned new Drosophila techniques, discussed project design and goals, worked on a review publication and a research publication, and collected data that will be followed up at Utica College. She has immediately set up a new Drosophila genetics unit in the course that she is teaching this fall at Utica College. Maggie worked an additional three weeks, collecting data, and learning some additional molecular procedures from others in the Messer Lab. Maggie now has a set of skills, and a better understanding of bench research; she will be applying to graduate school in neuroscience this fall. Both Julie and Maggie also interacted extensively with other Wadsworth faculty, students, postdocs, and several other undergraduates in our summer program. They also received Bioethics training from an outside speaker.
Jobs Summary: Summer Intern - Generate data w/intrabody/HD flies plus small molecules - New Hire, Research Scientist II - Conduct research on combinatorial Huntington's Disease therapy - new hire (Total jobs reported: 1)
Project Status: Completed
This award's data was last updated on Jul. 20, 2009. Help expand these official descriptions using the wiki below.