Despite years of intense efforts, there has been no effective therapeutic approach for Huntington's disease (HD) or other neurodegenerative diseases. The cause of toxicity in HD is poorly understood, and there is no well-defined drug target. Thus, at-risk and affected individuals inexorably progress toward clinical disease, providing an underlying urgency not only to find therapies for the disease, but also to develop biomarkers to predict the progress of therapeutic outcome. During the last funding period, we have discovered a toxic oxidation cycle in which there is cooperation between the mutant HD protein and the expansion mutation in causing toxicity. Toxicity occurs at four steps, and we have developed promising inhibitors to each one. The most promising compound, XJB-5-131, has a mitochondrial targeted antioxidant properties. Although it is poorly soluble, administration alone alleviates all of the obvious pathological features of disease in an hHdH150Q mouse model for HD. In the renewal, we propose to improve the drug-like properties of XJB-5-131 and use an optimized analog in a """"""""multi-hit"""""""" therapy in which multiple steps of the toxic oxidation cycles are targeted simultaneously: (1) a tricyclic pyrone for inhibiting the protein aggregates, (2) inhibitors for 8-oxo-G glycosylase, an enzyme that prevents single strand breaks and stops CAG trinucleotide expansion in DNA, and (3) HDAC inhibitors that target MSH2-MSH3, a protein that stabilizes the DNA loops to create expansions.
In Aim 1, we propose to co-administer our most successful compound, XJB-5-131, with at least one of the other inhibitors to determine the pharmacology, the optimal route of analog administration, the maximum tolerated dose of each inhibitor combination, and to prioritize in vivo testing according to the best drug-like properties.
In Aim 2, we will test the efficacy of multi-hit treatment using simple in vivo endpoints of motor function, cognition, histopathology, and mitochondrial activity to follow therapeutic progression. We will identify which combination of compounds is most effective in offsetting toxicity due to expression of the mutants HD protein. In sum, there are no therapies for HD or methods to speed up the search for therapeutics. New tools and approaches are desperately needed. Our novel discovered compounds and the multi-hit strategy for therapy provide a promising therapeutic approach that warrants further testing to fill these medical gaps.

Public Health Relevance

There are no therapies for Huntington's Disease or methods to speed up the search for therapeutics. At-risk and affected individuals inexorably progressing toward clinical disease provide an underlying urgency, not only to find therapies for the disease, but also to develop biomarkers to predict the progress of therapeutic outcome. We propose a multi-hit combination therapy to discover inhibitors of HD toxicity. Our novel discovered compounds, the two-hit strategy for therapy, and our new chemical fingerprint tool are rigorous and promising methods, and the use of all in our proposed research will fill these medical gaps.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS060115-07A1
Application #
8786204
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2007-07-01
Project End
2019-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$548,295
Indirect Cost
$223,013
Name
Lawrence Berkeley National Laboratory
Department
Type
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
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Polyzos, Aris A; McMurray, Cynthia T (2017) Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts. DNA Repair (Amst) 56:144-155
Polyzos, Aris; Holt, Amy; Brown, Christopher et al. (2016) Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes. Hum Mol Genet 25:1792-802
Budworth, Helen; McMurray, Cynthia T (2016) Problems and solutions for the analysis of somatic CAG repeat expansion and their relationship to Huntington's disease toxicity. Rare Dis 4:e1131885
Lai, Yanhao; Budworth, Helen; Beaver, Jill M et al. (2016) Crosstalk between MSH2-MSH3 and pol? promotes trinucleotide repeat expansion during base excision repair. Nat Commun 7:12465
Budworth, Helen; Harris, Faye R; Williams, Paul et al. (2015) Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease. PLoS Genet 11:e1005267
McMurray, Cynthia T; Vijg, Jan (2014) Editorial overview: Molecular and genetic bases of disease: the double life of DNA. Curr Opin Genet Dev 26:v-vii
Lee, Do-Yup; McMurray, Cynthia T (2014) Trinucleotide expansion in disease: why is there a length threshold? Curr Opin Genet Dev 26:131-40
Platt, Virginia; Lee, Do Yup; Canaria, Christie A et al. (2013) Towards understanding region-specificity of triplet repeat diseases: coupled immunohistology and mass spectrometry imaging. Methods Mol Biol 1010:213-30
Budworth, Helen; McMurray, Cynthia T (2013) Bidirectional transcription of trinucleotide repeats: roles for excision repair. DNA Repair (Amst) 12:672-84

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