This project aims to investigate the use of intrabodies in Huntington's disease (HD) therapy. HD is one of several neurodegenerative polyglutamine diseases caused by expansion of an unstable CAG triplet repeat. It is an autosomal dominant disorder affecting 1 in 10,000 individuals, with 30,000 cases and another 150,000 people at risk in the U.S. alone. There is currently no effective treatment no effective treatment for the polyglutamine diseases to ameliorate the neuropathological symptoms, which include emotional, behavioral, cognitive, intellectual, and motor components. Preventing aberrant interactions of mutant huntingtin with other proteins in neurons may be feasible by administration of a huntingtin-specific antibody fragment, an intrabody. Intrabodies are currently being tested in clinical trials for cancer treatment, and have shown promise for treatment of HIV and other infectious diseases. Previous work in our laboratory has shown that a huntingtin-specific intrabody previous aggregate formation of a mutant huntingtin fragment in vitro, indicative of inhibition of self-interactions. Since self-interactions may be analogous to huntingtin's deleterious interactions with other proteins, blocking elf-interactions may also inhibit the pathogenic protein-protein interactions. However, intrabody therapy for neurodegenerative disorders requires a vehicle for delivery across the blood-brain barrier. Research has demonstrated that the transferrin receptor system is a useful method for transport of materials from the circulation to the brain, but the details of this mechanism are undefined. Conjugation of an intrabody to such a vehicle for brain delivery will allow analysis of the effectiveness of this mode of treatment in the HD transgenic R6/2 mouse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS043033-02
Application #
6622375
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (20))
Program Officer
Oliver, Eugene J
Project Start
2002-01-03
Project End
Budget Start
2003-01-03
Budget End
2004-01-02
Support Year
2
Fiscal Year
2003
Total Cost
$27,578
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204