# GSK3 beta study in patients with Myotonic Dystrophy 1

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $446,321

## Abstract

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.

## Key facts

- **NIH application ID:** 9850544
- **Project number:** 5R01AR073379-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** LUBOV T TIMCHENKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,321
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850544

## Citation

> US National Institutes of Health, RePORTER application 9850544, GSK3 beta study in patients with Myotonic Dystrophy 1 (5R01AR073379-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9850544. Licensed CC0.

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