Duchenne muscular dystrophy

Duchenne muscular dystrophy is the most common neuromuscular disease in children. It affects one in 3,500 boys at birth.

What is Duchenne muscular dystrophy?

Duchenne muscular dystrophy is a genetic disease that causes progressive degeneration of all the body’s muscles. It is caused by an abnormality in the dystrophin gene located on the X chromosome. Non-expression or abnormal expression of a dystrophin causes muscle fiber fragility, resulting in progressive and irreversible destruction of muscle tissue. Symptoms are generally detected in early childhood, with loss of walking generally between the ages of 10 and 13, and respiratory assistance becoming necessary from adolescence onwards. Cardiac muscle damage is life-threatening. Duchenne muscular dystrophy strikes 150 to 200 new boys every year in France. This genetic and hereditary pathology almost exclusively affects boys, with girls being affected in exceptional cases.

Duchenne muscular dystrophy: Genethon’s role

Genethon has conducted out several projects aimed at treating Duchenne Muscular Dystrophy.

The most advanced product to date is GNT-0004, the result of collaboration between teams at Genethon and the Institute of Myology (Paris), with the University of London (Prof. George Dickson, Royal Holloway) and Caroline Le Guiner’s team (Nantes Gene Therapy Laboratory – Inserm/Université de Nantes/CHU de Nantes). This product is based on the use of an AAV (Adeno Associated Virus) vector carrying the transgene coding for a micro-dystrophin , since the very large size of the dystrophin gene means that it is technically impossible to insert the complete dystrophin DNA in this type of vector.
The gene therapy treatment envisaged is therefore based on the single administration of a gene coding for a shortened but functional form of this protein.

This treatment is aimed at all DMD patients, whatever the genetic abnormality at the root of their disease.

Duchenne muscular dystrophy: what’s happening today?

As part of the clinical development of this gene therapy, Généthon initiated a natural history study project of DMD in 2019 to better understand the high heterogeneity of the clinical picture of patients suffering from DMD within the same age group (5 to 9 years).

This study aims to better understand the longitudinal evolution of this pathology between 6 months and 3 years, and will collect individual data from DMD patients included according to pre-defined and standardized criteria. The aim of this study is to better comprehend the sensitivity of the functional scales used in this study to confirm the choice of methodologies to be taken into account in the gene therapy trial in patients with DMD. Each patient included in the natural history study will be considered as their own control in the gene therapy trial.
In 2023, 73 patients are already included in France and the United Kingdom with a 6-month follow-up for 54 of them. The purpose of this study is to recruit a total of about 140 patients whose duration of participation will be between 6 months and 3 years.

In parallel to the natural history study, a gene therapy protocol for young DMD-affected boys aged 6 to 10 years was approved by the French National Agency for Safety of Medicines and Health Products (ANSM) in France and the Medicines and Health Products Regulatory Agency (MHRA) in Great Britain, respectively at the end of 2020 and beginning of 2021.
A phase I/II/III clinical trial has therefore started in early 2021 in France and the United Kingdom.

In April 2021, the trial, which had begun in France, was suspended due to a serious adverse event in a patient treated with GNT-0004. Genethon investigated the cause of this event and proposed modifications to the protocol to the health authorities. The modified protocol was approved by the ANSM on March 1, 2022 and by the MHRA in the UK on March 16, 2022.

Since 2022, 4 additional patients have been treated, and the data generated were reviewed by the Data Monitoring Committee (DMC) in March 2024, which considered the intermediate dose tested to be the optimal dose having demonstrated a pharmacodynamic effect (microdystrophin protein expression 8 weeks post-treatment), as well as good tolerance with a proven clinical benefit.

As a result, the committee recommended continuing development of GNT-0004 by initiating the pivotal phase III trial at the determined optimal dose. At the same time, consultation with the European Agency for the Evaluation of Medicinal Products (EMA) enabled Genethon to validate the main aspects of the pivotal phase, as well as the analysis methodology to be applied.

Today, Genethon is actively preparing the pivotal phase of the trial, which is due to start in Q2 2025.

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