Flagship projects

Developing new gene therapies for Steinert disease

GT4DM: developing gene therapies that directly target the cause of myotonic dystrophy type 1 

Arnaud Klein, PhD

GT4DM is developing several gene therapy strategies designed to act directly on the mechanism responsible for myotonic dystrophy type 1, by targeting the mutant RNA produced by the DMPK gene.

Scientific challenge

Myotonic dystrophy type 1 (DM1), also known as Steinert disease, is a multisystem genetic disease that varies widely from one patient to another, and no treatment currently corrects its cause. The toxic RNA that accumulates in cells disrupts many biological processes, causing muscle, cardiac, respiratory or cognitive involvement. Acting on this central mechanism is one of the most promising avenues for slowing down or stabilising the disease.

© Image – Center of Research in Myology

Key questions to unravel

The team aims to determine how to neutralise the mutant RNA or its effects, and which strategies can achieve a lasting correction in the affected tissues. The goal is to identify the most effective approaches to prevent its production, promote its clearance or restore the disrupted cell functions.

Scientific and methodological approach

Three complementary strategies are being developed: 

  • blocking the production of the mutant RNA, using tools inspired by CRISPR or synthetic proteins able to target the DMPK gene precisely; 
  • degrading the toxic RNA, using a therapeutic RNA designed to recognise it and eliminate it before it accumulates; 
  • releasing the MBNL protein, which is trapped by the mutant RNA, using a “decoy” approach that prevents this sequestration. 

These treatments are delivered by modified viral vectors, then evaluated in cell and animal models to test their efficacy and safety.

These approaches are still at the preclinical stage, but some already have robust proof of concept in cell or animal models of the disease. One of them is more advanced and is undergoing preclinical development in collaboration with Généthon, with the aim of preparing the regulatory steps required before any possible move to human trials. Beyond myotonic dystrophy type 1, this work could also help to better understand and treat other genetic diseases linked to abnormal repeat sequence expansions in DNA.

Arnaud Klein, researcher at the Center of Research in Myology

Expected impact on research and clinical practice

GT4DM could pave the way for treatments able to slow down or stabilise the progression of DM1 by acting directly on its cause. The knowledge generated could also benefit other genetic diseases linked to repeat sequence expansions. One of the approaches has already entered advanced preclinical development in collaboration with Généthon.