Flagship projects

Overcoming the limits of gene therapy in ALS

GIANT: making gene therapy more precise, safer and longer lasting in ALS

The GIANT project seeks to move beyond the current limits of gene therapy in amyotrophic lateral sclerosis (ALS), by improving how the treatment is targeted, reducing adverse effects and ensuring that efficacy is sustained over time.

Scientific challenge

ALS rapidly destroys motor neurons and there is still no curative treatment. Gene therapy offers a promising avenue, but its use in adults remains difficult: reaching the nervous system requires high doses, which cause toxicity and immune responses, and tissues can dampen the effect of the treatment over time. Understanding and overcoming these barriers is essential if such therapies are to become genuinely usable.

Key questions to unravel

The team wants to identify the mechanisms that limit the efficacy of gene therapy: difficulty in reaching target cells, immune reactions, epigenetic responses that “switch off” the treatment, and the complexity of the disease itself. The aim is to design strategies able to act on several fronts in order to achieve a lasting benefit.

Scientific and methodological approach

The researchers will develop more precise vectors, able to reach diseased cells at lower doses. They will then analyse how tissues respond to the treatment, in particular the epigenetic and immune mechanisms that can reduce its effect. Finally, they will test combined approaches in order to act simultaneously on several dimensions of the disease and to prolong therapeutic efficacy.

The obstacles we are seeking to remove, namely dose, tolerance and loss of efficacy, are found in many similar diseases. By overcoming them, we open the way to more reliable treatments, able to act on several mechanisms of the disease and to bring a lasting improvement to patients’ lives.
Piera Smeriglio †, researcher at the Center of Research in Myology of the Institute

Expected impact on research and clinical practice

GIANT could make gene therapy safer and more effective in adults, by reducing the doses required and stabilising the effect of the treatment over time. This approach could slow the progression of ALS over the long term and improve patients’ quality of life. The solutions developed could also benefit other neuromuscular diseases facing the same obstacles.

† Following the recent death of Piera Smeriglio, the project is being continued by her team and a new scientific leader will be announced shortly