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.
| Miller, Todd W; Zhou, Chun; Gines, Silvia et al. (2005) A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease. Neurobiol Dis 19:47-56 |
