The treatment strategy for HIBCH deficiency targeting mitochondrial dysfunction

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09610
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: Yamada Kenichiro 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 主任研究員 (30291173)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: HIBCH欠損症 / ミトコンドリア / バリン代謝 / グルタチオン

Outline of Final Research Achievements

In HIBCH deficiency, methacrylyl-CoA, an intermediate product of valine metabolism, accumulates in mitochondria of multiple tissues. Methacrylyl-CoA reacts with thiol compounds (e.g., cysteamine, cysteine and reduced glutathione (GSH)) and essential cysteine residues of mitochondrial enzymes, including multiple respiratory chain enzymes and pyruvate dehydrogenase complex, and reduces their activities. This leads to cell damage, especially in the basal ganglia, by dramatically decreasing the cellular reduction state and reducing ATP production. In this study, we analyzed patient’s lymphoblasts, and found that the survival rate of patient’s lymphoblasts decreased during culture with a low glucose medium. Using this condition, we evaluated the therapeutic effect (maintaining of the survival rate) of candidate drugs for HIBCH deficiency. We found that one candidate drug that increases intracellular GSH levels restored the survival rate of patient lymphoblasts.

Free Research Field

先天性代謝疾患