Bev Hartig Huntington Disease Foundation Inc

Programs: Jodi mcbride at the oregon health and science university/oregon national primate research center, portland, or this project involved adult rhesus macaques that were injected with huntington's disease to validate neuroimaging measurements used to stage hd pathology in human subjects, generate new therapeutic biomarkers of disease progression and provide a second general viral-vector based monkey model of hd which would be made available to the research community for evaluation of promising therapeutics. In 2018, results were presented to the heredity disease foundation and at the annual chdi meeting of hd researchers

myriam heiman - mit - a common pathological feature of a number of neurodegenerative diseases, including huntington's disease (hd), is the selective vulnerability of nerve cell (neuronal) subpopulations to cell death. While the genetic underpinning of hd has been identified as mutations in the huntingtin gene, the specific cellular pathways leading to neuronal loss in hd remain unknown. Knowledge of these cellular pathways would lead to new therapeutic opportunities. We have recently developed an unbiased genertic method that allows us to identify genetic modifiers that enhance or supress mutant huntingtin protein toxicity in different subtypes of neurons in mouse models of hd. Using this method, we have found several genes that we believe regulate the toxic accumulation of mutant huntingtin in the brain. These include the gene nme1, which we hypothesize suppresses mutant huntington toxicity, and the gene il6, which we hypothesize enhances mutant huntingtin toxicity. The objective of our research is to on, a single-gene basis, test the mechanisms of their modulation of mutant huntingtin toxicity as well as the therapeutic effects of modulating these genes in mouse models of hd.

matt disney - scripts - we are designing and developing drug-like small molecules to target r(cag)exp and ameliorate its associated toxicity. We have demonstrated in preliminary studies that this approach is viable in hd cells (kumar et al. Chemical correction of pre-mrna splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(cag)-containing transcripts. Acs chemical biology (2012), 7(3), 496-505. Doi: 10. 1021/cb200413a). Additionally, we solved the 3- dimensional structure of the r(cag) repeats (see: yildirim et al. A dynamic structural model of expanded r(cag) repeats: a refined x-ray structure and computational investigations using molecular dynamics and umbrella sampling simulations. Journal of the american chemical society (2013), 135(9), 3528-38. Doi: 10. 1021/ja3108627). Thus, we have the expertise to develop lead drugs towards hd and also the means to understand how these drugs bind to the target by using the structural information. Our proposed work focuses using these studies as a launching point to develop even more potent, blood-brain barrier penetrant compounds to study hd biology and accelerate treatments to the clinic. These drug-like compounds can be applied to a novel strategy that we developed that allows an rna repeat expansion to synthesize its own inhibitors in cells. That is, the disease-causing r(cag) repeat that causes hd would be custom synthesize its own drugs only in hd-affected cells and tissues. Thus, our improved compounds will be implemented in such an approach. If successful, we would have a very precise medicine that only targets hd cells, while leaving healthy cells untouched.