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

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

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.
 
Description Data Blitz Talk at Edinburgh Neuroscience Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 5 min data blitz talk at Edinburgh Neuroscience Day on my PhD project (selected abstract)
Year(s) Of Engagement Activity 2020
 
Description Science Chat @ Grassmarket 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Science Chat @ Grassmarket: science communication event organised by the Intersci student society from Edinburgh University at the Grassmarket Community Project, leading a one-hour conversation about my work, answering questions, linking research to the news and explaining complex biological concepts in layman's terms. Raising awareness about Spinal Muscular Atrophy, motor neuron disease, gene therapy, biomedical research in general.
Year(s) Of Engagement Activity 2019
 
Description Student Experience Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Invited speaker at an event organised by the University of Edinburgh for visiting students from Zheijang university - talk about student experience and my research to date
Year(s) Of Engagement Activity 2020