Huntington's disease (HD) is caused by the expression of the toxic mutant huntingtin protein (mthtt). Huntingtin is also the most salient molecular target for disease modifying therapy and indeed treatments that target its production, processing, or turnover are under development. Measurement of mthtt has broad potential as a biomarker. Its levels in blood could correlate to disease activity, severity, or stage;changes in its levels could provide a pharmacodynamic marker for therapies directly or indirectly modulating huntingtin. We recently helped develop a bioassay for measuring soluble mutant huntingtin levels utilizing time-resolved Forster Resonance Energy Transfer (trFRET). In preliminary studies applying the assay to blood in HD mice and human HD, it is highly sensitive for soluble mutant huntingtin in tissues and cellular fluids and detects it in blood from premanifest and manifest HD subjects. Through our NIH supported Program Project (P01- NS058792, Biomarkers for Huntington's Disease: accelerating the development of therapies), we are accumulating blood samples from large populations of controls, premanifest HD, manifest HD subjects, and HD subjects participating in therapeutic trials. In this application, we are seeking to optimize and validate this assay, ready it for GLP use, and assess how blood levels of huntingtin change with the development of symptoms, with progression of symptoms, and in response to a potential neuroprotective treatment. This accelerated review PAR is appropriate because it depends on subjects and blood samples from active single and multi-center clinical research studies supported by NIH including REVEAL-HD, PRECREST, PHAROS, and CREST-E observational and therapeutic trials.

Public Health Relevance

Huntington's disease (HD) is caused by a genetic abnormality in the huntingtin protein. Many potential treatments for HD are in development that target huntingtin protein. To help monitor whether such treatments are working and whether they can slow down HD, we have developed the first blood test that measures levels of mutant huntingtin. We propose to optimize this test and to use it to help several large NIH supported studies meet their goals.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Sutherland, Margaret L
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Massachusetts General Hospital
United States
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Huntington Study Group Reach2HD Investigators (2015) Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 14:39-47
Moscovitch-Lopatin, Miriam; Goodman, Rachel E; Eberly, Shirley et al. (2013) HTRF analysis of soluble huntingtin in PHAROS PBMCs. Neurology 81:1134-40
Weiss, Andreas; Grueninger, Stephan; Abramowski, Dorothée et al. (2011) Microtiter plate quantification of mutant and wild-type huntingtin normalized to cell count. Anal Biochem 410:304-6
Moscovitch-Lopatin, Miriam; Weiss, Andreas; Rosas, Herminia Diana et al. (2010) Optimization of an HTRF Assay for the Detection of Soluble Mutant Huntingtin in Human Buffy Coats: A Potential Biomarker in Blood for Huntington Disease. PLoS Curr 2:RRN1205