Embryonic disease manifestation and treatment in a mouse model of spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality and disability, affecting one in every 6,000-10,000 babies born worldwide (Groen, Talbot & Gillingwater 2018 Nature Reviews Neurology). SMA is caused by low levels of the survival motor neuron (SMN) protein throughout the body, which leads to nerve cell death and muscle wasting. In 2016/2017, the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) both approved the first therapy for use in SMA patients (known as nusinersen or SpinrazaTM) (Finkel et al., 2017 New England Journal of Medicine). This therapy acts by boosting levels of SMN protein in the nervous system. In clinical trials, nusinersen clearly delivered benefits for many patients. However, a lot of patients did not respond to the treatment, and some of those that did respond only showed modest improvements. Data from pre-clinical animal studies and emerging data from ongoing clinical trials strongly suggest that treatment efficacy can be improved by treating earlier in the disease (before birth), indicative of an important time window during which therapy can be effective (Foust et al., 2010 Nature Biotechnology; Lutz et al., 2014 Journal of Clinical Investigation).
The Gillingwater lab has an ongoing project delivering SMN-targeted therapies to SMA mice still in the womb ('in utero'). Our hypothesis is that in utero delivery of SMN-targeted therapies will provide a significant improvement in treatment efficacy over traditional post-natal delivery. However, the cellular and molecular landscape of disease pathogenesis in SMA mice has yet to be fully characterized.
Aims:
Using a range of morphological and molecular techniques, the student will undertake a comprehensive evaluation of the cellular and molecular landscape of disease pathogenesis in pre-natal SMA mice. We will initially explore pathological changes occurring in the spinal cord, brain, muscle, heart and liver of SMA mice, compared to littermate controls. This will be complemented by a state-of-the-art proteomics screen that will investigate molecular changes at the single protein level in each of these tissues. Finally, we will explore how pre-natal delivery of SMN-therapies modifies/corrects these changes.