Gene therapy is particularly exciting because it addresses the root cause of a disease, rather than targeting downstream pathological mechanisms. It is therefore often perceived as offering greater therapeutic potential than more conventional approaches. Moreover, the prospect of a one-shot treatment, potentially providing long-lasting benefits after a single administration, is particularly attractive to patients and families.

However, does this promise always translate into clinical reality? To explore this question, we will examine three different scenarios in the field of neuromuscular disorders: spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), and X-linked myotubular myopathy (XLMTM). These three examples illustrate both the remarkable advances achieved through gene therapy and the limitations that have emerged along the translational pathway.

We will discuss the challenges at multiple levels, from molecular mechanisms, vector delivery and tissue targeting to clinical efficacy, safety and long-term outcomes. We will also address the medico-economic dimension, including the sustainability, affordability and accessibility of these highly innovative treatments. Finally, we will explore the ethical challenges raised by gene therapies, particularly in a context where high expectations, sometimes fuelled by the promise of a one-shot cure, may exceed what current science and clinical evidence can realistically deliver.