# Mechanisms and Therapeutic Options of Hypersomnia in Myotonic Dystrophy

> **NIH NIH R21** · STANFORD UNIVERSITY · 2020 · $438,627

## Abstract

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.

## Key facts

- **NIH application ID:** 9977456
- **Project number:** 1R21NS109775-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** SEIJI NISHINO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,627
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977456

## Citation

> US National Institutes of Health, RePORTER application 9977456, Mechanisms and Therapeutic Options of Hypersomnia in Myotonic Dystrophy (1R21NS109775-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9977456. Licensed CC0.

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