Making ‘mini-muscles’ to test potential treatments for Duchenne muscular dystrophy

Dr Saverio Tedesco

Dr Tedesco and his PhD student aim to develop 3D ‘mini-muscles’ in the laboratory as a model of Duchenne muscular dystrophy. These will be developed from iPS cells from people with the condition. This research will provide an important tool to screen for effective treatments.

Our project will combine cutting-edge technologies such as gene editing and muscle tissue engineering to develop an innovative patient-specific tool to study DMD and test experimental treatments.

What are the aims of this project?

Duchenne muscular dystrophy can be caused by different mutations in the dystrophin gene, all leading to loss of the dystrophin protein. In recent years several new types of therapy have been developed to increase the amount of dystrophin in muscle cells. However, one of the greatest challenges in getting these new therapies to the clinic is having appropriate models to test them in.

In this project Dr Tedesco and his PhD student aim to make patient-specific human 3D ‘mini-muscles’ in the laboratory using human induced pluripotent stem (iPS) cells. iPS cells are made by taking cells from the body, such as skin cells, and genetically ‘reprograming’ them so that they can be developed into any type of cell in the body. Importantly, these mini-muscles will contain a novel genetic tool that will enable the researchers to measure the presence of dystrophin in the cells.

Firstly, the researchers will generate iPS cells from people with and without Duchenne muscular dystrophy. The researchers will use molecular scissors to add a ‘reporter’ to the dystrophin gene, which will then allow them to precisely measure the amount and size of dystrophin present in the cell.

Next, Dr Tedesco and his student will produce muscle fibres, blood vessels and other cells found in muscle tissue from the iPS cells. These different cell types will be combined and grown in a 3D ‘scaffold’ in a dish to produce patient-specific artificial ‘mini-muscles’. The researchers will analyse and compare the structure and function of the ‘mini-muscles’ to make sure they are an accurate model of muscles in the body and Duchenne muscular dystrophy.

Finally, the researchers will test different potential therapies in the mini-muscles using the novel ‘reporter’ system to measure response to treatment. They will look to see if the treatments increase the amount of dystrophin and improve the function of the mini-muscles developed from the cells of people with different mutations in the dystrophin gene.

Why is this research important?

Testing how safe and effective treatments are in mouse models is an important step before clinical trials in humans, but mice may not respond to a treatment in the same way as humans. Therefore, a model of human muscle that can be used by researchers in the laboratory would be a valuable tool to identify and develop effective potential treatments for Duchenne muscular dystrophy.

Moreover, having a reliable method to measure the amount of dystrophin following treatment could be important to understand differences in the response to new treatments caused by different mutations of the dystrophin gene.

How will the outcomes of this research benefit people with Duchenne muscular dystrophy?

This research could provide a tool to identify and develop effective treatments. Importantly, because the cells will be from people with different mutations in the dystrophin gene, this research could inform us if different treatments are more effective for people with certain mutations. It will then allow researchers to develop treatments accordingly.

This research could reduce the need for muscle biopsies to test the effect of a treatment because the cells needed to make iPS cells can be obtained through less invasive procedures, such as a blood sample.

How might this research impact on other neuromuscular conditions?

The technology used to make ‘mini-muscles’ and the reporting system could be transferred to other neuromuscular conditions. It would then be possible to study the mini-muscles and test treatments for other neuromuscular conditions.

Grant Information

Project leader: Dr Francesco Saverio Tedesco
Institute: University College London (UCL)
Conditions: Duchenne muscular dystrophy
Duration: Four years, starting 2017
Total cost (£): 115,836
Official title: A human iPS cell-derived artificial skeletal muscle for DMD therapy development

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