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A Novel HDAC6 Inhibitor, CKD-504, is Effective in Treating Preclinical Models of Huntington’s Disease
Endan Li1,# (Research Fellow), Jiwoo Choi1,# (Graduate Student), Hye-ri Sim3 (Senior Researcher), Jiyeon KIm1 (Graduate Student), Jae Hyun Jun3 (Researcher), Jangbeen Kyung3 (Team Leader), Nina Ha3 (Director), Semi Kim3 (Team Leader), Keun Ho Ryu3 (Senior Director), Seung Soo Chung4 (Professor), Hyun Sook Kim5 (Professor), Sungsu Lee5 (Researcher), Wongi Seol5 (Director), Jihwan Song 1,5,* (Professor & CEO)
1Department of Biomedical Science, CHA University, Seongnam 13488, Korea,
2CKD Research Institute, Chong Kun Dang Pharmaceutical Corp., Yongin 16995, Korea,
3Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Korea,
4Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea,
5Stem Cell & Regenerative Medicine Institute, iPS Bio, Inc., Seongnam 13488, Korea
Huntington’s disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of メ-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 model of HD to test the effect of a novel HDAC6 selective inhibitor, CKD-504, developed by Chong Kun Dang (CKD Pharmaceutical Corp., Korea). We found that treatment of CKD-504 increased tubulin acetylation, microtubule stabilization, axonal transport, and the decrease of mutant huntingtin protein in vitro. From in vivo study, we observed CKD-504 improved the pathology of Huntington’s disease: alleviated behavioral deficits, increased axonal transport and number of neurons, restored synaptic function in corticostriatal (CS) circuit, reduced mHTT accumulation, inflammation and tau hyperphosphorylation in YAC128 TG mouse model. These novel results highlight CKD-504 as a potential therapeutic strategy in HD.
Abstract, Accepted Manuscript(in press) [Submitted on October 23, 2022, Accepted on January 2, 2023]
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