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.
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.
|Polyzos, Aris A; McMurray, Cynthia T (2017) The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington's disease. Mech Ageing Dev 161:181-197|
|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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