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 gene-targeted 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 SMNtargeted 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, SMN-targeted 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 highresolution 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.