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Genome surgery for Duchenne muscular dystrophy

This project is designed to produce a stable permanent and universally-applicable genetic correction of the dystrophin gene. Genome surgery, as the name implies, involves the cutting of DNA with special molecular scissors and using new pieces of DNA to stitch the ends together again. In terms of this project, the aim is to introduce a cut in the X-chromosome DNA near the start of the dystrophin gene and then introduce a new piece of DNA that is designed to allow the synthesis of normal 'healthy' dystrophin protein. Since we are conducting the 'genome surgery' near the start of the dystrophin gene, this approach is designed to correct virtually all types of mutations that cause Duchenne muscular dystrophy and may thus provide a treatment that could help virtually all patients. Additionally, this therapy would be administered as a single one-off treatment since it is the natural gene itself that is being targeted and 'corrected' and the changes made would be permanent and stable.

During this PhD studentship, research on this type of 'molecular scissors' system for dystrophin genome surgery has been conducted as follows:

Design and manufacture of the 'scissors' to cut the start of the dystrophin gene.
Delivery and introduction of the 'scissors' into the muscle cells, and examination for effective cutting of the dystrophin gene on the X-chromosome.
Design of new healthy pieces of DNA to stitch back together and repair the dystrophin gene.
Work will be starting soon to combine the scissors with the new repair DNA to correct the gene in cultured muscle stem cells from Duchenne muscular dystrophy patients.

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Developing gene therapy for Duchenne muscular dystrophy

Developing a gene therapy for Duchenne muscular dystrophy Professor George Dickson and his team plan to develop a novel gene therapy approach that is aimed at delivering a functional, full-size dystrophin gene to muscle cells using a harmless virus.

So far research has been restricted to delivering smaller mini- or micro-dystrophin genes due to restrictions in the size of the DNA fragment that the virus can accommodate. In this project the researchers will use two or three viruses each carrying a different part of the dystrophin gene. In the muscle cell the different parts assemble to form the blueprint to produce a full size dystrophin protein. If successful this approach could be used to treat people with Duchenne as well as people with Becker muscular dystrophy.

This project is aimed to develop an advanced gene therapy for Duchenne muscular dystrophy. Adeno-associated viruses (AAVs) are harmless and can be used as gene therapy agents to deliver dystrophin 'micro-genes' to Duchenne muscular dystrophy muscle. But these AAV viruses have a limit to the size of the 'gene load' they can accommodate.

For example, a full-sized natural dystrophin gene cannot be accommodated in a single virus. We have shown that two or three viruses used together can overcome this size limitation. Or the natural dystrophin gene can be split between three viruses and when a mixture of all three is injected they combine to produce full size natural dystrophin protein. In the first year of the project, we designed and made these dual and triple AAV virus systems for dystrophin gene therapy.

In the current year, we have:
1) Developed new ways to produce these viruses, increasing the amounts of virus that can be manufactured
2) Identified chemicals which help produce viruses carrying a large load and increase their ability to deliver dystrophin gene therapy to muscle.
3) Designed new dystrophin gene controls switches which produce high levels of dystrophin in heart as well as muscle.

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Genome Surgery
Gene Therapy
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