A novel HDAC6 inhibitor, CKD-504, is effective in treating preclinical models of huntington’s disease

다국어 초록 (Multilingual Abstract)

Huntington’s disease (HD) is a neurodegenerative disorder, ofwhich pathogenesis is caused by a polyglutamine expansion inthe amino-terminus of huntingtin gene that resulted in the aggregationof mutant HTT proteins. HD is characterized by progressivemotor dysfunction, cognitive impairment and neuropsychiatricdisturbances. Histone deacetylase 6 (HDAC6), amicrotubule-associated deacetylase, has been shown to inducetransport- and release-defect phenotypes in HD models, whilsttreatment with HDAC6 inhibitors ameliorates the phenotypiceffects of HD by increasing the levels of α-tubulin acetylation,as well as decreasing the accumulation of mutant huntingtin(mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics.
In this study, we employed in vitro neural stem cell(NSC) model and in vivo YAC128 transgenic (TG) mouse modelof HD to test the effect of a novel HDAC6 selective inhibitor,CKD-504, developed by Chong Kun Dang (CKD PharmaceuticalCorp., Korea). We found that treatment of CKD-504 increasedtubulin acetylation, microtubule stabilization, axonaltransport, and the decrease of mutant huntingtin protein invitro. From in vivo study, we observed CKD-504 improved thepathology of Huntington’s disease: alleviated behavioral deficits,increased axonal transport and number of neurons, restoredsynaptic function in corticostriatal (CS) circuit, reduced mHTTaccumulation, inflammation and tau hyperphosphorylation inYAC128 TG mouse model. These novel results highlight CKD-504as a potential therapeutic strategy in HD.

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