GSK3β as a Drug Development Target for DM1

Published on Sun, 01/07/2018

Clinical Trials Targeting GSK3β

AMO Pharma is in clinical development with AMO-2 (tideglusib), an inhibitor of GSK3β signaling, for congenital myotonic dystrophy (CDM). A single blind, phase 2 trial has been initiated at Newcastle University to evaluate drug safety and efficacy in adolescent and adult patients with congenital and juvenile-onset DM1 (see

Studies from Dr. Lubov Timchenko and colleagues provided the initial preclinical rationale for the GSK3β target in a mouse model of DM1 (Jones et al., 2012). AMO’s clinical development of the GSK3β inhibitor, tideglusib, was, in part, based on these preclinical data. The GSK3β—cyclin D3—CUGBP1 pathway is of particular interest for CDM because of the potential role CUGBP1 plays in myogenesis. Now, additional studies have been undertaken to validate this novel target for drug development in CDM.

Evaluation of a GSK3β Inhibitor in Young HSALR Mice

Dr. Timchenko and colleagues at Cincinnati Children’s Hospital, Baylor College of Medicine, Centre Hospitalier–Université Laval Research Center, and Mount Sinai Hospital (Toronto) conducted evaluations of the validity of the GSK3β inhibition strategy in young (1.5 month old) HSALR mice. Two GSK3β inhibitors (6-bromoindirubin-39-oxime (BIO) and indirubin) were administered to mice, ip every 48 hours for 6 weeks. The group reported that early correction of GSK3β signaling was important for differentiation and long-term integrity of HSALR mouse skeletal muscle. Their data showed that correction of GSK3β—cyclin D3—CUGBP1 pathway activity was instrumental in the structural and functional changes in skeletal muscle. Using a Celf1 knockout model, the research team further established the connection between CUGBP1 levels and skeletal muscle development.

Relevance for Clinical Trials with Tideglusib

This latest study focuses on the validity of the GSK3β target for DM, as measured by changes in muscle histopathology and functional grip strength. These preclinical data show that the GSK3β target may be capable of modulating the progression and severity of the disease. However, differences in the drug employed and delivery regimen in this mouse study mean that it did not evaluate the efficacy of the tideglusib drug as a candidate therapeutic for DM. Rigorously-designed studies of tideglusib will be important to support the case for DM1 therapy development.


Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.
Wei C, Stock L, Valanejad L, Zalewski ZA, Karns R, Puymirat J, Nelson D, Witte D, Woodgett J, Timchenko NA, Timchenko L.
FASEB J. 2017 Dec 4. pii: fj.201700700R. doi: 10.1096/fj.201700700R. [Epub ahead of print]

GSK3β mediates muscle pathology in myotonic dystrophy.
Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT.
J Clin Invest. 2012 Dec;122(12):4461-72. doi: 10.1172/JCI64081. Epub 2012 Nov 19.