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-GSK3?-CUGBP1 axis. We found that the activity of CUGBP1 is regulated by GSK3?-cyclin D3-CDK4 pathway and that the mutant CUG repeats alter CUGBP1 activity by the pathological increase of GSK3? 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 GSK3?-CUGBP1 pathway in human patients? materials, are needed to further support the clinical trial using TG. My application will examine the GSK3??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 GSK3? 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 GSK3?.

Public Health Relevance

Myotonic Dystrophy type 1 is a devastating disease without cure. This disease affects adult patients (classic DM1) and newborn babies (congenital DM1). We propose to examine GSK3? kinase as a potential therapeutic target and an outcome treatment molecule in patients with congenital and adult DM1. The proposed studies are highly important translational steps to the GSK3-based clinical trials in adult and congenital DM1.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Cheever, Thomas
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Cincinnati Children's Hospital Medical Center
United States
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