Innovating spinal muscular atrophy models in the therapeutic era

Abstract

Spinal muscular atrophy (SMA) is a severe, monogenetic, neuromuscular disease. A thorough understanding of its genetic cause and the availability of robust models has led to the development and approval of three gene-targeting therapies. This is a unique and exciting development for the field of neuromuscular diseases, many of which remain untreatable. The development of therapies for SMA not only opens the door to future therapeutic possibilities for other genetic neuromuscular diseases, but also informs us about the limitations of such treatments. For example, treatment response varies widely and, for many patients, significant disability remains. Currently available SMA models best recapitulate the severe types of SMA, and these models are genetically and phenotypically more homogeneous than patients. Furthermore, treating patients is leading to a shift in phenotypes with increased variability in SMA clinical presentation. Therefore, there is a need to generate model systems that better reflect these developments. Here, we will first discuss current animal models of SMA and their limitations. Next, we will discuss the characteristics required to future-proof models to assist the field in the development of additional, novel therapies for SMA.

Promoting expression in gene therapy: more is not always better

“…However, AAV9 expression in mouse models is not always directly translatable to humans. This 2nd generation vector will therefore also need further testing in more models of SMA (Signoria et al, 2023 ), including non-human primates, and eventually in clinical trials.…”