Spinal Muscular Atrophy is a genetic motor neuron disease with a childhood onset. In its most severe form, it causes progressive paralysis and death before 2 years of age. Recent exciting developments in the field have led to the approval of 3 gene targeted treatments for SMA. These treatments are allowing children who would have died, to live. However, impactful deficits often remain, and patients are often left with chronic disability. There is therefore an urgent need to develop new drugs which can work in synergy with existing treatments to enhance regeneration of the neuromuscular system and protect remaining motor neurons.
Neuromuscular junctions (NMJs), the connections between muscle and nerve breakdown early in disease. We have recently used mouse models of SMA to show that following treatment, the recovery of the NMJs is incomplete and there is capacity for improved recovery.
In this project, we plan to test whether new drugs can enhance recovery of NMJs in a mouse model of SMA. We will test both FDA approved compounds and novel targets which have been shown to enhance regeneration of NMJs in other contexts. We will administer the gene targeted approved drug (i.e. an viral gene therapy) and then also give a test compound. We will then assess the effect on recovery of motor ability, weight gain, motor neuron loss and health/number of NMJs. This project will involve administration of substances to a mouse model of SMA, phenotypic evaluation, mouse dissection and immunofluorescent staining and quantification of surrogates of neuromuscular pathology in mouse tissue.
The SMA research field is at a truly exciting juncture where we are transitioning from an acute degenerative emergency to understanding and treating chronic disability. It offers huge opportunity for known and novel neuroprotective compounds to have dramatic effects on patient outcomes. We hope that by developing these new approaches for SMA, they will also have benefit in other neuromuscular and neurodegenerative conditions, and thereby also benefit a wider group of patients in the future.