DNA vaccine prevents diabetic phenotype in Huntington disease murine model.

2003 JUL 9 - (NewsRx.com & NewsRx.net) -- by Maria G. Essig, MS, ELS, senior medical writer - A DNA vaccine against the toxic intracellular proteins involved in Huntington disease prevented the development of diabetes in the HDR6/2 mouse model for Huntington disease, according to a report in the journal Molecular Therapy.

"Immunization against extracellular neurotoxic proteins has shown promise in the treatment of several neurodegenerative disorders," stated Todd W. Miller and colleagues at the State University of New York-Albany. "We sought to determine whether immunization against mutant huntingtin, the intracellular protein that causes Huntington's disease (HD), could slow disease progression in the HD mouse model HDR6/2.

"Diabetes mellitus occurs at an increased frequency in patients with Huntington's disease, one of a variety of unrelated genetic diseases associated with the biomarker of impaired glucose tolerance. In addition to neurological symptoms and weight loss, a diabetic phenotype has been observed in the HD transgenic mouse model HDR6/2 expressing human HD exon 1 with >144 CAG repeats. We hypothesized that an anti-huntingtin immune response could ameliorate or correct this HDR6/2 phenotype."

The investigators developed a DNA vaccine using pHD103-GFP, a plasmid that encoded a N-terminal fragment of huntingtin fused to a fluorescent protein (GFP). Mice were immunized with pHD103-GFP or a plasmid control (pGFP). Eighteen of the 30 mice immunized with pHD103-GFP had an antibody response at a serum dilution of 1:100. Plasma glucose control was restored in those mice that produced an antibody response to HD plasmid vaccination.

"The diabetic correction that we observed occurred in the absence of an apparent change in aggregates, in agreement with the previous suggestions that aggregates are not correlated with neuronal loss in HD brain and that aggregates may actually indicate a cellular protective mechanism," said Miller and his collaborators.

Insulin staining of pancreatic tissue from untreated ...