The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, 8410501 Israel.
Department of Pediatric Neurology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410101 Israel.
Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2217831120. doi: 10.1073/pnas.2217831120. Epub 2023 Feb 6.
Myopathy is the main adverse effect of the widely prescribed statin drug class. Statins exert their beneficial effect by inhibiting HMG CoA-reductase, the rate-controlling enzyme of the mevalonate pathway. The mechanism of statin myopathy is yet to be resolved, and its treatment is insufficient. Through homozygosity mapping and whole exome sequencing, followed by functional analysis using confocal microscopy and biochemical and biophysical methods, we demonstrate that a distinct form of human limb girdle muscular disease is caused by a pathogenic homozygous loss-of-function missense mutation in HMG CoA reductase (), encoding HMG CoA-reductase We biochemically synthesized and purified mevalonolactone, never administered to human patients before, and establish the safety of its oral administration in mice. We then show that its oral administration is effective in treating a human patient with no significant adverse effects. Furthermore, we demonstrate that oral mevalonolactone resolved statin-induced myopathy in mice. We conclude that mutation causes a late-onset severe progressive muscular disease, which shows similar features to statin-induced myopathy. Our findings indicate that mevalonolactone is effective both in the treatment of hereditary myopathy and in a murine model of statin myopathy. Further large clinical trials are in place to enable the clinical use of mevalonolactone both in the rare orphan disease and in the more common statin myopathy.
肌病是广泛应用的他汀类药物的主要不良反应。他汀类药物通过抑制 HMG CoA 还原酶（甲羟戊酸途径的限速酶）发挥其有益作用。他汀类药物肌病的发病机制尚未解决，其治疗方法也不足。通过纯合子定位和外显子组测序，然后使用共聚焦显微镜和生化及生物物理方法进行功能分析，我们证明了一种独特形式的人类肢体带肌病是由 HMG CoA 还原酶（）的致病性纯合失活功能错义突变引起的，该基因编码 HMG CoA 还原酶。我们生化合成并纯化了以前从未在人类患者中使用过的甲羟戊酸内酯，并确定了其在小鼠中的口服给药安全性。然后我们表明，其口服给药在治疗无明显不良反应的人类患者中是有效的。此外，我们证明了口服甲羟戊酸内酯可有效治疗小鼠的他汀类药物诱导的肌病。我们得出结论， 突变导致一种迟发性严重进行性肌肉疾病，其特征与他汀类药物诱导的肌病相似。我们的研究结果表明，甲羟戊酸内酯不仅对遗传性 肌病有效，而且对他汀类药物肌病的小鼠模型也有效。进一步的大型临床试验正在进行中，以便在罕见的孤儿病和更常见的他汀类药物肌病中能够临床应用甲羟戊酸内酯。
