GSK3 beta study in patients with Myotonic Dystrophy 1

强直性肌营养不良患者的 GSK3 beta 研究 1

• 批准号: 10326843
• 负责人: LUBOV T TIMCHENKO
• 金额: $ 29.7万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326843
• 关键词: 19q; 3' Untranslated Regions; Address; Adult; Affect; Antisense Oligonucleotides; Anxiety; Biochemical; Biopsy; Blood; Blood specimen; CDK4 gene; CUG repeat; Childhood; Chromosomes; Clinical Research; Clinical Trials; Complex; Development; Disease; Family; Fibroblasts; Genes; Goals; Growth; Human; Infant; Knowledge; Left; Length; Link; Mediating; Messenger RNA; Modification; Molecular; Molecular Analysis; Monitor; Multicenter Studies; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Atrophy; Myoblasts; Myofibroblast; Myopathy; Myotonia; Myotonic Dystrophy; Myotonic dystrophy type 1; Neuromuscular Diseases; Newborn Infant; Pathologic; Pathology; Pathway interactions; Patients; Penetrance; Phase; Phase I/II Clinical Trial; Phenotype; Phosphotransferases; Pilot Projects; Publishing; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Severities; Severity of illness; Signal Transduction; Skeletal Muscle; Skin; Solid; Testing; Therapeutic; Time; Treatment outcome; base; biopharmaceutical industry; clinical development; cohort; cyclin D3; improved; in vivo; inhibitor; mouse model; mutant; novel therapeutic intervention; postnatal; prevent; small molecule; therapeutic target

Myotonic Dystrophy type 1 (DM1) is a complex neuro-muscular disease, caused by an expansion of CTG repeats in the 3’ UTR of DMPK gene on the chromosome 19q. The longest CTG expansions affect infants causing congenital DM1 (CDM1). CTG repeats cause DM1 pathology through alterations of several RNA- binding proteins including CUGBP1 and MBNL1. The phase I/II clinical trial, testing the degradation of the mutant DMPK mRNA by antisense oligonucleotide (AON) has been recently completed. Unfortunately, it was found that further modifications of AONs are required to improve their penetrance to skeletal muscle. Therefore, there is an urgent need for development of alternative therapeutic approaches based on small molecules. My lab is working with the development of a novel therapeutic approach for the treatment of CDM1 and DM1 which is based on the correction of RNA processing (including splicing) that is mis-regulated by CUG n-GSK3β-CUGBP1 axis. We found that the activity of CUGBP1 is regulated by GSK3β-cyclin D3-CDK4 pathway and that the mutant CUG repeats alter CUGBP1 activity by the pathological increase of GSK3β kinase. The inhibitors of GSK3 significantly reduce DM1 muscle pathology in a mouse model of DM1 (HSA mice) and improve growth and neuromotor activity in CDM1 mouse model (DMSXL mice). These basic findings created a strong background for the first, the GSK3-based clinical study for adult patients with CDM1. The Phase IIa of this trial with the inhibitor of GSK3 tideglusib (TG) was recently completed by a biopharmaceutical company AMO Pharma with encouraging results. Although the trial is in transition to the Phase II/III in pediatric CDM1, much more mechanistic studies, including molecular analysis of the GSK3β-CUGBP1 pathway in human patients’ materials, are needed to further support the clinical trial using TG. My application will examine the GSK3β-CUGBP1 pathway in muscle biopsies, myofibrobasts and blood samples from DM1 and CDM1 patients with variable disease severity (Aim 1). We will also study if GSK3β was corrected in CDM1 patients treated with TG. We will determine if the treatments with TG recover MBNL1 activity correcting global splicing abnormalities in DM1 (Aim 2). All pathways affected by TG treatments will be defined. One more critical issue will be addressed in my application. We recently found that the TG-treatments of DM1 myoblasts and fibroblasts derived from patients with 200-400 CTG repeats reduce the levels of the mutant DMPK mRNA. We propose to examine if TG improves degradation of the mutant DMPK regardless of the length of CTG expansions (Aim 3). If TG improves the degradation of the mutant DMPK mRNA in DM1 and CDM1 myoblasts and fibroblasts with long expansions, the inhibitors of GSK3 will represent small molecules targeting the prime cause of CDM1 and DM1. The obtained knowledge will be critical for the further development of clinical trials of CDM1 and DM1 that are based on the correction of GSK3β.

强直性肌营养不良1型(DM1)是一种复杂的神经肌肉疾病，由CTG的扩张引起 在染色体19q的DMPK基因3‘端非编码区重复。最长的CTG扩张会影响婴儿 导致先天性DM1(CDM1)。CTG重复通过几个RNA的改变引起DM1病理- 结合蛋白包括CUGBP1和MBNL1。I/II期临床试验，测试 最近，反义寡核苷酸(AON)突变DMPK基因的研究已经完成。不幸的是，它是 研究发现，需要对AON进行进一步的修饰，以提高其对骨骼肌的透过性。 因此，迫切需要开发基于Small的替代治疗方法 分子。我的实验室正在开发一种治疗CDM1的新方法。 以及DM1，它基于CUG错误调节的RNA加工(包括剪接)的纠正 N-GSK3-β-CUGBP1轴。我们发现，CUGBP1的活性受Gsk3、β-Cyclin D3-CDK4调节 GSK_3β病理性升高对CUG重复序列活性的影响 激活剂。GSK3抑制剂显著减轻DM1(HSA)小鼠模型的DM1肌肉病理 并改善CDM1小鼠模型(DMSXL小鼠)的生长和神经运动活性。这些基本发现 为第一个基于GSK3的成人CDM1患者的临床研究创造了坚实的背景。这个 最近，一家生物制药公司完成了这项试验的IIa阶段，该试验使用的是GSK3替德鲁西布(Tg)的抑制剂 AMO Pharma公司业绩令人鼓舞。虽然这项试验正在过渡到儿科的II/III阶段 CDM1，更多的机制研究，包括对GSK3β-CUGBP1途径的分子分析 人类患者的材料，需要进一步支持使用TG的临床试验。我的申请表将审查 肌活检组织、肌成纤维细胞和DM1、CDM1GSK_3β-CUGBP_1信号通路 疾病严重程度不同的患者(目标1)。我们还将研究CDM1患者的GSK3β是否得到纠正 用甘油三酯治疗。我们将确定使用TG的处理是否恢复了纠正全局剪接的MBNL1活性 DM1异常(目标2)。所有受TG治疗影响的途径都将被定义。还有一个关键问题 将会在我的申请表中注明。我们最近发现，对DM1成肌细胞的TG处理和 来自具有200-400个CTG重复的患者的成纤维细胞降低了突变的DMPK mRNA的水平。我们 建议检查TG是否改善突变的DMPK的降解，而不考虑CTG的长度 扩展(目标3)。If TG促进DM1和CDM1成肌细胞中突变DMPK mRNA的降解 和长时间扩张的成纤维细胞，GSK3的抑制剂将代表靶向质点的小分子。 CDM1和DM1的原因。所获得的知识将是进一步发展临床试验的关键 Cdm1和Dm1是基于Gsk3β的校正。