Novel therapies for neuromuscular diseases with altered phosphoinositide metabolism

磷酸肌醇代谢改变的神经肌肉疾病的新疗法

• 批准号: 397787655
• 负责人: Professor Volker Haucke, Ph.D.
• 金额: --
• 依托单位: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397787655?language=en
• 关键词: Novel; therapies; neuromuscular; diseases; altered

Phosphoinositides (PIs) are small lipid molecules found on different compartments inside of the cell. Their amounts and location in cells are tightly regulated and balanced by proteins called kinases and phosphatases. Mutations in the genes that make several of these proteins have been described in an emerging group of rare childhood genetic diseases including forms of epilepsy, brain malformations, neuropathy, and muscle disease. As a group, these diseases are associated with severe symptoms and, in many cases, early death, and none have treatments. Our goal is find therapies for these devastating disorders. We are particularly focused on diseases associated with mutations in myotubularins, termed MTMopathies. Myotubularins are PIs phosphatases, and mutations in the genes that encode them are associated with severe forms of childhood muscle and nerve disorders. Specifically, mutations in myotubularin (or MTM1) cause X-linked myotubular myopathy (XLMTM) and mutations in myotubular related protein 2 (or MTMR2) cause a form of Charcot-Marie-Tooth neuropathy (CMT4B1). We have shown using both cell and animal models of these diseases that not having either MTM1 or MTMR2 cause accumulation of certain phosphoinositide lipids and that, in turn, cause disease. We then discovered that normalizing the levels of these phosphoinositide lipids by genetically removing the kinases that act opposite myotubularins can dramatically improve features of animals models of these diseases, including even completely reversing them. Based on these results, we hypothesized that chemicals that inhibit these kinases can treat these disorders. In this proposal, we will test this hypothesis by identifying drugs that act against these kinases and then investigating them in well defined models of XLMTM and CMT4B1. We will use 3 different strategies for developing such inhibitors (medicinal chemistry, industrial partnership, and drug repurposing screen), and will test and validate them using a pipeline that includes both cell culture and zebrafish models. Promising kinase inhibitors will then be examined to see whether they can rescue/reverse the abnormalities we observe in our mouse models of human MTMopathies; such models have previously been developed by members of the consortium. Successful drugs will be amenable to rapid translation to patients to be potentially tested in clinical trials, and could provide the first meaningful therapy for these severe diseases of childhood. In addition, our work will lay the groundwork for considering similar approaches for the other neurogenetic diseases associated with abnormalities in how PIs are made or broken down, and will greatly advance the understanding of these conditions.

磷酸肌苷（pi）是在细胞内不同隔室中发现的小脂质分子。它们在细胞中的数量和位置受到一种叫做激酶和磷酸酶的蛋白质的严格调节和平衡。在一组罕见的儿童遗传疾病中，包括癫痫、脑畸形、神经病变和肌肉疾病，已经描述了制造这些蛋白质的基因突变。作为一个群体，这些疾病与严重的症状有关，在许多情况下，早期死亡，没有一种是可以治疗的。我们的目标是找到治疗这些毁灭性疾病的方法。我们特别关注与肌小管蛋白突变相关的疾病，称为MTMopathies。肌管蛋白是PIs的磷酸酶，编码它们的基因突变与儿童肌肉和神经疾病的严重形式有关。具体来说，肌小管蛋白（或MTM1）的突变导致x连锁肌小管肌病（XLMTM），肌小管相关蛋白2（或MTMR2）的突变导致Charcot-Marie-Tooth神经病变（CMT4B1）。我们已经通过这些疾病的细胞和动物模型表明，没有MTM1或MTMR2会导致某些磷酸肌醇脂质的积累，而这反过来又会导致疾病。然后我们发现，通过基因去除与肌小管蛋白相反的激酶，使这些磷酸肌肽脂质的水平正常化，可以显著改善这些疾病的动物模型的特征，甚至完全逆转它们。基于这些结果，我们假设抑制这些激酶的化学物质可以治疗这些疾病。在本提案中，我们将通过鉴定对这些激酶起作用的药物，然后在定义良好的XLMTM和CMT4B1模型中研究它们来验证这一假设。我们将使用3种不同的策略来开发此类抑制剂（药物化学，工业合作伙伴关系和药物再利用筛选），并将使用包括细胞培养和斑马鱼模型在内的管道来测试和验证它们。有希望的激酶抑制剂将被检查，看看它们是否可以挽救/逆转我们在人类mtmopathy小鼠模型中观察到的异常；这样的模型以前是由该联盟的成员开发的。成功的药物将能够快速转化为患者，进行潜在的临床试验，并可能为这些严重的儿童疾病提供第一个有意义的治疗方法。此外，我们的工作将为考虑类似的方法来治疗其他与pi如何产生或分解异常相关的神经遗传疾病奠定基础，并将极大地促进对这些疾病的理解。

项目成果

Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

• DOI: 10.1038/s41467-020-16696-6
• 发表时间: 2020-06
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Linda Sawade;F. Grandi;Marianna Mignanelli;G. Patiño-López;K. Klinkert;F. Langa-Vives;Roberta Di Guardo;A. Echard;A. Bolino;V. Haucke

Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy

• DOI: 10.1073/pnas.2009469118
• 发表时间: 2021-03-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Guerrero-Valero, Marta;Grandi, Federica;Bolino, Alessandra
• 通讯作者: Bolino, Alessandra