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）和相关的快速眼动（REM）改变