Characterising pre-clinical models and testing gene therapy for X-linked spinal muscular atrophy

XL-SMA is a type of SMA that causes progressive muscle weakness, mainly in boys. It is caused by changes in the UBA1 gene. People with XL-SMA normally have a lack of reflexes (areflexia) and muscles, joints or tissues which become stiff and hard to move (known as contractures). Not much is known about this form of SMA, and there are no animal models are available for it. This makes research into new treatments more challenging.

Professor Gillingwater and his research team previously identified the potential of targeting UBA1 for therapies for all genetic forms of SMA. They have developed UBA1-targeted therapies but have been unable to test them due to the lack of animal models. Working with the Medical Research Council’s Genome Editing Mice for Medicine programme, Professor Gillingwater and his team have now developed a mouse model for XL-SMA, which will be characterised and used in this study.

This project aims to understand the symptoms and features of the recently developed XL-SMA mouse model developed by Professor Gillingwater and colleagues. It’s important to know how mice with XL-SMA behave and how strong their muscles are, compared to mice without this condition. Once done, UBA1-targeted therapy will be tested on this model to investigate if the therapy is a viable treatment for XL-SMA.

Little is known about the biology of XL-SMA. This has partly been due to the lack of animal models. This research will lead to a full characterisation of the first animal model of this condition, which will then be used for testing the first potential therapy for XL-SMA.

In the first year of the project, the researchers were able to show that the XL-SMA mouse model has the symptoms observed in people with XL-SMA, suggesting that this is a model can be used to mimic the condition. This now means the researchers can use the model to test potential treatments of XL-SMA, including the UBA1-targeted therapy the team have developed.