End of project summary
Microdystrophin is a short version of dystrophin, often forming a base of gene therapy that aims to restore the missing dystrophin in people with Duchenne muscular dystrophy. And while microdystrophin expression in skeletal muscle (muscles that help us move) has shown some benefits for people with the condition, the same was not observed in the heart.
Prof Morgan and colleagues have previously observed that microdystrophins are unable to interact with cavin proteins (mainly cavin-1) in the heart, which could potentially explain why the benefit of gene therapy cannot be observed in the heart. Cavin proteins are important for the heart to work properly.
During her PhD studies, Elena Marrosu, under the supervision of Prof Jenny Morgan and Dr Federica Montanaro, showed that the loss of dystrophin leads to the unusual distribution of cavins -1 and -4 in the heart muscle cells of mice. The correct localisation is critical for heart muscle cells to be fully functional.
Interestingly, Elena was able to show that microdystrophin cannot rescue the function of cavins in the heart. This leads to the conclusion that microdystrophin lacks important regions required for association with cavins. And while that exact region is yet to be identified, the researchers were able to eliminate other regions within microdystrophin, narrowing down the potential area involved in the association with cavins. This will enable the improved design of microdystrophins, considering the specific effects in the heart.
This project will increase our understanding of the role of dystrophin in the heart and how the lack of dystrophin leads to heart disease in Duchenne and Becker muscular dystrophy patients. This new knowledge will provide the basis for making gene therapy approaches even more effective.
Dr Montanaro, University College London, says:
Basic research such as this project is the only way to develop next-generation gene therapy products that address all key life-threatening symptoms, and offer a more effective and comprehensive treatment to those with Duchenne and Becker muscular dystrophies.
In the first five months of the project, the PhD student has produced and tested the antibodies needed to investigate the interactions between dystrophin and proteins found in the caveolae. Antibodies recognise and bind to specific proteins. They can be used to detect where a protein is in a cell, how much there is and if it binds to other proteins. Antibodies detect specific parts of a protein, so can even tell the difference between full length and micro-dystrophin.
The student has also been trained in a technique called electron microscopy (EM). This technique will allow them the researchers to look at the structure of the tiny caveolae in high detail. So far they have studied the caveolae in heart cells from healthy mice. Next they will use EM to look at caveolae in the heart cells from mouse models of DMD and mice that have been treated with a micro-dystrophin. The researchers will then compare the caveolae to see if they are damaged or different. These experiments are important to get a better understanding of what causes the cardiac symptoms in DMD and BMD.
What are the aims of the project?
This project will specifically look at the interaction between dystrophin, and a protein called cavin-1. Cavin-1 is important in organizing specialized regions on the surface of cardiac cells called caveolae. These regions are important in controlling the contraction of heart muscle.
Dr Montanaro and her team have discovered that dystrophin interacts with cavin-1 and in this project will bring together the expertise of Professor Morgan and Dr Montanaro’s teams to investigate the interaction in more detail. Specifically, they will study the interaction of normal dystrophin protein with caveolae in the heart and determine how this is affected by a loss of dystrophin. This will be done using mice that are healthy, and those that have symptoms of Duchenne muscular dystrophy, as well as heart cells generated from induced pluripotent stem cells (iPSCs) from a person with Duchenne muscular dystrophy.
They will also identify the parts of dystrophin protein that bind to cavin-1; this information will be used to design an improved gene therapy.
Gene therapy uses a virus to deliver a working version of the dystrophin gene to all muscles of the body, including the heart. As the dystrophin gene is extremely large it must be shortened before it can fit into the virus. This shortened version is called a micro-dystrophin and it is important the micro-dystrophin has all the domains it needs to function well. Existing micro-dystrophins have the essential parts for improving function in limb muscles, but it is not clear which parts are needed for good heart function.
The interaction between dystrophin and cavin-1 that Dr Montanaro and her team have identified is lost in Duchenne muscular dystrophy and may not be restored by currently available micro-dystrophins. The aim is to design a new micro-dystrophin that includes the parts of the gene needed for cavin-1 interaction in the hope that this will have a restorative effect on heart function.
Why is this research important?
This research will inform the development of gene therapy products for people with Duchenne or Becker muscular dystrophy, leading to better designed micro-dystrophin genes that could improve heart function as well as limb function.
With gene therapy approaches for Duchenne muscular dystrophy entering clinical trials, this research offers timely and valuable information for enhancing the therapeutic effects of micro-dystrophins.
How will the outcomes of this research benefit people with Duchenne muscular dystrophy?
People with Duchenne or Becker muscular dystrophy could benefit from gene therapy, which introduces a functioning copy of the dystrophin gene into their muscles. Existing gene therapy approaches are expected to increase limb strength and increase mobility, but these benefits will be limited if heart function is still compromised.
Developing new micro-dystrophins with enhanced therapeutic benefits in the heart could improve heart function in people with Duchenne or Becker muscular dystrophy, allowing them to live longer and more active lives.
How might this research impact on other neuromuscular conditions?
The work in this project will lead to a better understanding of muscle structure and function, specifically how caveolae function in healthy heart muscle. There may also be wider implications of the research, as disruption of caveolae has been reported in limb girdle muscular dystrophy (type 1C) and FSHD.
Grant Information
Project leader: Professor Jenny Morgan
Institute: University College London
Conditions: Duchenne muscular dystrophy, Becker muscular dystrophy
Duration: four years, starting 2017
Total cost (£): 118,275
Official title: Characterization of a novel interaction of dystrophin with caveolae in the heart
Further information
Read about our other Duchenne muscular dystrophy research projects
Read our research news stories on Duchenne muscular dystrophy
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