DNA vaccination against mutant huntingtin ameliorates the HDR6/2 diabetic phenotype.
Immunization against extracellular neurotoxic proteins has shown promise in the treatment of several neurodegenerative disorders. 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. DNA vaccination was used to present the mutant intracellular antigen to the immune system in a physiological context. Assay of a peripheral biomarker, pancreatic insufficiency, was used as an initial test of efficacy. DNA vaccination with a 5' fragment of the HD cDNA prevented development of the HDR6/2 diabetic phenotype. Insulin staining demonstrated that HDR6/2 diabetes may be caused by a severe pancreatic insulin deficiency. Immunoresponsive HDR6/2 mice showed increased insulin staining more closely resembling wild-type levels. These observations suggest that DNA vaccination against toxic intracellular proteins may be therapeutic.
Miller
Todd W
TW
Department of Biomedical Sciences, State University of New York at Albany, 12203, USA.
Shirley
Thomas L
TL
Wolfgang
William J
WJ
Kang
Xiaowei
X
Messer
Anne
A
D000818:Animals; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D010188:Exocrine Pancreatic Insufficiency; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000628:therapy*; D007111:Immunity, Cellular; D007328:Insulin / Q000172:deficiency; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D014611:Vaccination; D019444:Vaccines, DNA / Q000627:therapeutic use*
D001786:Blood Glucose; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007328:Insulin; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019444:Vaccines, DNA; D049452:Green Fluorescent Proteins