Developing the next generation of therapies for the childhood motor neuron disease, spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the SMN1 gene. Excitingly, SMA has recently moved into a therapeutic era, with an approved SMN genetargeted therapy (nusinersen/Spinraza™) that improves many aspects of disease, including motor function and survival. This has catapulted SMA to the forefront of neuromuscular disease research, providing a unique opportunity to improve outcomes for patients whilst facilitating study of the impact of therapies on underlying disease biology. Importantly,
however, clinical data concerning SMN-targeted therapies demonstrate that the current situation only represents the beginning of the journey for therapy development, rather than the end. SMN-targeted therapies improve key disease parameters including motor function and survival in many patients, but they remain far from representing a “cure”. Instead, SMNtargeted therapies are modifying the natural progression of the disease, leading to a need to develop a ‘next-generation’ of combinatorial therapies (“SMN-plus”) for SMA.
This project will utilise a range of techniques and approaches (including high-resolution microscopy and molecular profiling techniques) to undertake pre-clinical research examining the potential benefits of combining SMN-dependent therapies with other therapies targeting
SMN-independent pathways in mouse models of SMA. We will assess their effectiveness on both neuromuscular and systemic pathology.