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（EDS）和快速眼动（REM）的相关改变 睡眠模式是强直性肌营养不良（DM）的最典型的非肌肉特征之一。 今天，没有办法改善DM1的神经症状。主要病理 DM脑的变化可归因于毒性RNA表达、肌盲样蛋白（Mbnl） C（C）UG扩增RNA的隔离和特异性选择性剪接事件的失调 正常成人中枢神经系统（CNS）功能所需的。我们最近证明了快速眼动 使用DM1的小鼠模型（即，Mbnl2 KO小鼠）。 由于婴儿型基因剪接在成人DM患者的许多基因中仍然存在，我们认为REM 糖尿病睡眠异常可能是婴儿型睡眠的残留。现有的人类数据表明， REM睡眠倾向的异常增加可能导致EDS。如果我们的假设是正确的， 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，一种FDA批准的抗生素， 和抑制其与MBNL结合的能力。红霉素减少病灶 形成和挽救的错剪接。此外，口服给药红霉素， 人类常用剂量显示剪接逆转和肌强直改善，无毒性 在DM1模型小鼠中。由于红霉素渗透到中枢神经系统，我们希望它能挽救 在中枢神经系统基因的错误剪接和正常化的睡眠异常DM1。因此我们将 我提出以下实验来验证我们的假设，并寻求新的治疗方案，为睡眠 和DM1的CNS异常。(1)在DMSXL中评估睡眠和行为表型 在成年期和早期阶段， （2）评价红霉素在小鼠脑中的RNA毒性逆转作用。 （3）评价红霉素是否使DMSXL小鼠的睡眠和CSN异常正常化 小鼠