Early epigenetic changes and transcriptional dysregulation have emerged as a potentially early and significant pathophysiological mechanism in several neurodegenerative disorders. In HD, multiple studies have demonstrated differences in epigenetic marks and in the expression of genes in distinct regions of postmortem tissue and genetic mouse models and support an important role in the pathogenesis of HD. Other studies have also demonstrated the potential therapeutic benefit of several different HDAC inhibitors in HD transgenic mice. In this study, we will measure regional changes in HDAC expression in vivo, in both prodromal and early symptomatic HD, using a novel PET ligand. We will evalaute the distribution of HDACs in HD, determine how early these changes are present, and correlate regional changes with clinical measures. Given the continued development of novel HDAC inhibitors for HD and other neurodegenerative disorders, measuring HDAC expression in vivo by PET would provide a critically needed target engagement and pharmacodynamics marker. .

Public Health Relevance

Early epigenetic changes and transcriptional dysregulation have emerged as a potentially early and significant pathophysiological mechanism in several neurodegenerative disorders, including in Huntington's disease (HD). In HD, differences in the expression of distinct genes have been reported in both transgenic and post-mortem brain studies. In this study, we will evaluate regional HDAC expression and its relationship to clinical symptoms, in vivo in HD, using a novel PET ligand, which may also provide a needed target needed target and pharmacodynamics marker.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS098407-02
Application #
9419328
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Miller, Daniel L
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code