Mechanisms and Therapeutic Options of Hypersomnia in Myotonic Dystrophy

强直性肌营养不良的嗜睡机制和治疗选择

• 批准号: 9977456
• 负责人: SEIJI NISHINO
• 金额: $ 43.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977456
• 关键词: Adult; Affect; Affinity; Alternative Splicing; Antibiotics; Antisense Oligonucleotides; Binding; Biological Markers; Brain; CUG repeat; Cell model; Cells; Characteristics; Congenital neurologic anomalies; Cytosine; Development; Disease; Dose; Erythromycin; Event; Excessive Daytime Sleepiness; FDA approved; Fibroblasts; Genes; Genetic Transcription; Guanine; Human; Hypersomnias; Impairment; Infant; Knockout Mice; Life; Modeling; Monitor; Mus; Muscle; Mutation; Myotonia; Myotonic Dystrophy; Myotonic dystrophy type 1; Nervous System Physiology; Neuraxis; Neurologic Symptoms; Oral Administration; Organ; Pathologic; Patients; Permeability; Phenotype; Proteins; REM Sleep; RNA; RNA Splicing; Reporting; Scientist; Skeletal Muscle; Sleep; Spliced Genes; Symptoms; Testing; Therapeutic; Thymine; Tissues; Toxic effect; Transcript; Transgenic Organisms; Trinucleotide Repeats; behavioral phenotyping; blind; experimental study; human data; medication safety; mouse model; mutant; response; sleep abnormalities; sleep pattern; small molecule; transgene expression

Excessive daytime sleepiness (EDS) and associated alterations in rapid eye movement (REM) sleep patterns are among the most characteristic non-muscular features of myotonic dystrophy (DM). Today there are no means to ameliorate the neurological symptoms of DM1. Major pathological changes in the DM brain are attributable to toxic RNA expression, muscleblind-like protein (Mbnl) sequestration by C(C)UG expansion RNAs, and dysregulation of specific alternative splicing events required for normal adult central nervous system (CNS) function. We recently demonstrated that REM sleep propensity is increased specifically in DM1, using mouse models of DM1 (i.e., Mbnl2 KO mice). Since infant type gene splicing remains in many genes of patients in adult DM, we believe that REM sleep abnormalities in DM may be a remnant of infant type sleep. Available human data suggest that abnormally increased REM sleep propensity may cause EDS. If our hypothesis is correct, we may be able to treat sleep abnormalities of DM patients by reducing RNA toxicity. Nakamori et al. recently reported that erythromycin, a FDA approved antibiotic, showed high affinity to CUG expansions and a capacity to inhibit its binding to MBNLs. Erythromycin decreased foci formation and rescued missplicing in DM1 cell. Furthermore, oral administrations of erythromycin at a dose commonly used in humans showed splicing reversal and improvement of myotonia with no toxicity in the DM1 model mice. Since erythromycin penetrates into the CNS, we expect that it rescues missplicing in genes in the CNS and normalize the sleep abnormalities in DM1. We will therefore propose the following experiments to test our hypothesis and seek new treatment options for the sleep and CNS abnormalities of DM1. (1) Evaluate sleep and behavioral phenotypes in the DMSXL transgenic (with human DMPK mutation) and littermate WT mice in adulthood and during early developmental periods, (2) Evaluate the RNA toxicity-reversing effect of erythromycin in the brain of the DMSXL mice and (3) Evaluate if erythromycin normalizes sleep and CSN abnormalities in the DMSXL mice.

白天过度嗜睡（ED）和快速眼动的相关改变（REM） 睡眠模式是肌发育症（DM）最有特征的非肌肉特征。 今天，没有能够改善DM1的神经系统症状。主要病理 DM脑的变化归因于有毒的RNA表达，肌肉盲蛋白（MBNL） c（c）ug膨胀RNA的固结以及特定替代剪接事件的失调 正常成人中枢神经系统（CNS）功能所需。我们最近证明了REM 使用DM1的小鼠模型（即MBNL2 KO小鼠），在DM1中特别增加了睡眠倾向。 由于在成人DM中，婴儿类型的基因剪接仍然保留在许多患者的基因中，因此我们认为REM DM的睡眠异常可能是婴儿型睡眠的残余。可用的人类数据表明 异常增加的REM睡眠倾向可能导致ED。如果我们的假设正确，我们可能是 能够通过降低RNA毒性来治疗DM患者的睡眠异常。 Nakamori等。最近报道，红霉素是FDA认可的抗生素，显示出高亲和力 cug膨胀和抑制其与MBNL的结合的能力。红霉素降低了焦点 在DM1细胞中形成并救出了失误。此外，在 人类通常使用的剂量表现出剪接逆转和肌瘤的改善，没有毒性 在DM1模型小鼠中。由于红霉素渗透到中枢神经系统中，我们希望它可以拯救 中枢神经系统中的基因失误，并使DM1的睡眠异常正常化。因此，我们会 提出以下实验来检验我们的假设并为睡眠寻求新的治疗选择 DM1的中枢神经系统异常。 （1）评估DMSXL中的睡眠和行为表型 转基因（带有人类DMPK突变）和同窝型wt小鼠在成年期和早期 发育期，（2）评估红霉素在大脑中的RNA毒性逆转作用 DMSXL小鼠和（3）评估红霉素是否使DMSXL的睡眠和CSN异常归一化 老鼠。