Intrabody Gene Therapy Effective in Mouse Models of Huntington's Disease

A highly specific intrabody (an antibody fragment specially modified to recognize a target in the cytoplasm or nucleus of a cell) has proven to be an effective agent for gene therapy in mouse models of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by a mutation in the gene that encodes for the huntingtin (Htt) protein. The mutated gene adds from one to many dozens of extra glutamine molecules to Htt. Incomplete breakdown of the enlarged protein results in the buildup of toxic peptides that destroy cells in the nervous system.

Investigators at the California Institute of Technology (Pasadena, USA) examined the possibility that specialized "intrabody" antibodies that target various sites on Htt could be used to treat Huntington's disease. They reported in the October 28, 2009, issue of the Journal of Neuroscience that one intrabody, Happ 1 gave promising results. Happ 1 recognized a proline-rich segment that is unique to Htt. In the current study, Happ 1 was introduced into the brains of five different Huntington's disease mouse models by a viral carrier.

Happ1 treatment conferred significant beneficial effects in a variety of assays of motor and cognitive deficits and strongly ameliorated the neuropathology found in several of the disease models. Moreover, Happ1 significantly prolonged the life span of one of the models.

"Gene therapy in these models successfully attenuated the symptoms of Huntington's disease and increased life span," said senior author Dr. Paul Patterson, professor of biological sciences at the California Institute of Technology. "Our studies show that the use of intrabodies can block the parts of mutant huntingtin that cause its toxicity without affecting the wild-type, or normal, huntingtin-or any other proteins."

"We need to improve the efficacy of the intrabody," said Dr. Patterson, "and we need to build a viral vector that can be controlled-induced and turned off-in case of unexpected side effects. This is a general goal shared by all types of experimental gene therapies."

Related Links:
California Institute of Technology