Speaker: Prof. Francesco Muntoni, University College London Great Ormond Street Institute of Child Health and Queen Square Institute of Neurology, London UK.

Title: Successes and limitations of current genetic therapies for Duchenne muscular dystrophies.

Host: Prof. Peter Zammit

Abstract: In the last decade there have been consistent advances in different approaches aimed at restoring muscle dystrophin production in patients with Duchenne muscular dystrophy. The earlier approaches focused on RNA therapies, with multiple splice-switching antisense oligonucleotides (ASOs), several of which having received conditional FDA approval, targeting specific “skippable” mutations. These efforts with first generation ASOs were generally well tolerated but resulted in low levels of restored dystrophin levels, requiring at least 3 years of weekly intravenous infusions to convincingly appreciate divergence from the natural history course of the disease. These early efforts are currently being followed by second generation ASOs, now in early clinical trials and demonstrating significantly higher levels of the surrogate dystrophin expression on muscle biopsy, while larger studies to demonstrate clinical efficacy are due to start this year. These new ASO have the advantage of requiring less common administrations, although there is limited long term data on their tolerability.

 

More recently the efforts have taken advantages of different adeno-associated viral vectors (AAV), which can deliver to muscle and heart a much smaller version of the dystrophin protein, a minidystrophin. At the time of writing, of the 5 ongoing DMD AAV gene therapies, one has received in June 2024 full FDA approval for ambulant DMD boys and conditional approval for non-ambulant DMD individuals, while another product also in June 2024 unexpectedly failed to demonstrate efficacy following a large phase 3 clinical trial and is being discontinued.

While the progress of AAV in DMD is extremely encouraging, there are also issues related to the very high viral load administered systemically and the associated immune responses that require close surveillance from treating physicians. Other unknowns that the field will have to better understand over the next few years relate to the efficiency of transduction in muscle with a different degree of pathology, hence if the same level of efficacy and in turn of risk/ benefit will be observed across the entire spectrum of the condition, and the long-term durability of these episomal viral vectors.

Despite these unknown these parallel programs of translational research have brought a high level of competition and innovation that is likely to benefit not only the DMD community but the wider neuromuscular field.

Event details

30 April 2025 12:45 to 14:00

Harris Lecture Theatre
Hodgkin Building
Great Maze Pond, London, SE1 9RT