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: 10593112
• 负责人: LUBOV T TIMCHENKO
• 金额: $ 20.2万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593112
• 关键词: 19q; 3' Untranslated Regions; Address; Adult; Affect; Antisense Oligonucleotides; 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; Severities; Severity of illness; Signal Transduction; Skeletal Muscle; Skin; Solid; Testing; Therapeutic; Time; Treatment outcome; anxiety reduction; biopharmaceutical industry; clinical development; cohort; cyclin D3; glycogen synthase kinase 3 beta; 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 扩张引起 19q 染色体上 DMPK 基因 3' UTR 中的重复 最长的 CTG 扩展影响婴儿。 先天性 DM1 (CDM1) 重复序列通过几个 RNA 的改变导致 DM1 病理学。 结合蛋白包括CUGBP1和MBNL1的I/II期临床试验，测试其降解情况。 不幸的是，最近已经完成了通过反义寡核苷酸（AON）突变DMPK mRNA。 发现需要对 AON 进行进一步修饰以提高其对骨骼肌的渗透性。 因此，迫切需要开发基于小分子的替代治疗方法。 我的实验室正在开发一种治疗 CDM1 的新型治疗方法。 DM1 基于对 CUG 错误调节的 RNA 加工（包括剪接）的校正 n-GSK3β-CUGBP1轴我们发现CUGBP1的活性受GSK3β-cyclin D3-CDK4调节。 突变体 CUG 重复通过 GSK3β 的病理性增加改变 CUGBP1 活性 GSK3 抑制剂可显着减少 DM1 (HSA) 小鼠模型中的 DM1 肌肉病理。 小鼠）并改善 CDM1 小鼠模型（DMSXL 小鼠）的生长和神经运动活动这些基本发现。 为第一项基于 GSK3 的 CDM1 成年患者临床研究奠定了坚实的背景。 这项 GSK3 tidglusib (TG) 抑制剂的 IIa 期试验最近由一家生物制药公司完成 AMO Pharma 公司取得了令人鼓舞的结果，尽管该试验正在过渡到儿科 II/III 期。 CDM1，更多的机制研究，包​​括 GSK3β-CUGBP1 通路的分子分析 需要人类患者的材料来进一步支持使用 TG 的临床试验，我的申请将进行检查。 DM1 和 CDM1 的肌肉活检、肌成纤维细胞和血液样本中的 GSK3β-CUGBP1 通路 我们还将研究 GSK3β 在 CDM1 患者中是否得到纠正。 我们将确定 TG 处理是否恢复 MBNL1 活性，纠正全局剪接。 DM1 中的异常（目标 2）将定义受 TG 治疗影响的所有途径。 我们最近发现 DM1 成肌细胞和 TG 治疗将在我的申请中得到解决。 来自具有 200-400 个 CTG 重复的患者的成纤维细胞降低了突变 DMPK mRNA 的水平。 建议检查 TG 是否可以改善突变体 DMPK 的降解，无论 CTG 的长度如何 如果 TG 改善了 DM1 和 CDM1 成肌细胞中突变 DMPK mRNA 的降解。 和具有长扩展的成纤维细胞，GSK3的抑制剂将代表针对主要的小分子 所获得的知识对于进一步开展 CDM1 和 DM1 的临床试验至关重要。 基于GSK3β修正的CDM1和DM1。

项目成果

Correction of RNA-Binding Protein CUGBP1 and GSK3β Signaling as Therapeutic Approach for Congenital and Adult Myotonic Dystrophy Type 1.

纠正 RNA 结合蛋白 CUGBP1 和 GSK3β 信号传导作为先天性和成人强直性肌营养不良 1 型的治疗方法。

• 发表时间: 2019-12-21
• 影响因子: 5.6
• 作者: Timchenko; Lubov
• 通讯作者: Lubov

Correction of Glycogen Synthase Kinase 3β in Myotonic Dystrophy 1 Reduces the Mutant RNA and Improves Postnatal Survival of DMSXL Mice.

强直性肌营养不良 1 中糖原合酶激酶 3β 的校正减少了突变 RNA 并提高了 DMSXL 小鼠的产后存活率。

• 发表时间: 2019-11-01
• 影响因子: 5.3
• 作者: Wang, Mei;Weng, Wen;Stock, Lauren;Lindquist, Diana;Martinez, Ana;Gourdon, Genevieve;Timchenko, Nikolai;Snape, Mike;Timchenko, Lubov
• 通讯作者: Timchenko, Lubov