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Gene mutation may hold key to muscular dystrophy treatment

16 November 2015
Appeared in BioNews 828

Researchers have discovered a gene linked to Duchenne muscular dystrophy (DMD) after a dog bred to model the disease was found to have a protective mutation against it.

The mutation was in a development gene called JAG1, which has never before been linked to muscular dystrophy. Scientists hope that this gene could be a target for new approaches to treating DMD.

'All the genetic therapies tested so far, with little success, have targeted the gene that codes for the protein dystrophin. We're presenting a different approach, which opens up a range of new possibilities,' said Professor Mayana Zatz, who co-led the study that was published in Cell.

Duchenne muscular dystrophy is a genetic disorder caused by a lack of dystrophin, a protein that helps to hold muscle fibres together. The gene coding for dystrophin is situated on the X chromosome, meaning DMD usually only affects males (but females can be carriers). It is the most common and most rapidly progressing type of muscular dystrophy; affected boys are typically wheelchair bound by 10–12 years old.

'Without special care, patients don't reach the age of 20. Nowadays, with assisted breathing, they may survive until they're 40 or beyond,' said Professor Zatz.

While most dystrophin-deficient dogs do not live past two years old, the mildly affected dog, Ringo, survived for 11 years, which is normal for his breed. One of Ringo's offspring inherited the JAG1 mutation and is currently nine years old.

Dystrophin-deficient dogs have also been the subjects of a gene-therapy study that aims to treat DMD by reintroducing a miniature version of the dystrophin gene.

'Due to its size, it is impossible to deliver the entire [dystrophin] gene with a gene therapy vector,' explained Professor Dongshen Duan, who led the gene therapy study that was published in Human Molecular Genetics.

He added: 'Through previous research, we were able to develop a miniature version of this gene called a microgene. This minimised dystrophin protected all muscles in the body of diseased mice.'

Professor Duan and his team have now demonstrated that a virus can be safely used to deliver micro-dystrophin to muscles of dystrophin-deficient dogs. The researchers injected the dogs with the virus when they were around two months old and beginning to show signs of DMD. The researchers found that the gene was present in skeletal muscle and the heart and diaphragm. The dogs are now six to seven months old and continuing to develop normally.

'The virus we are using is one of the most common viruses; it is also a virus that produces no symptoms in the human body, making this a safe way to spread the dystrophin gene throughout the body,' said Professor Duan.

He added: 'These dogs develop DMD naturally in a similar manner to humans. It's important to treat DMD early before the disease does a lot of damage as this therapy has the greatest impact at the early stages in life.'

Gene Therapy for Muscular Dystrophy Advances
Voice of America |  22 October 2015
Gene Therapy Treatment for Muscular Dystrophy Effective in Dogs
Genetic Engineering and Biotechnology News |  23 October 2015
Gene therapy treats all muscles in the body in muscular dystrophy dogs
Eurekalert (press release) |  22 October 2015
Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype
Cell |  12 November 2015
Puppy bred to have muscular dystrophy saved by surprise mutation
Nature News |  12 November 2015
Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus
Human Molecular Genetics |  15 October 2015
Target gene identified for therapies to combat muscular dystrophy
Eurekalert (press release) |  12 November 2015
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