There have been a series of exciting headlines in the news in the last week or so about a radical new gene-therapy for Duchenne Muscular Dystrophy, and how this research in dogs might lead to a cure for the condition… but what have the scientists actually done? How realistic is the hype? Why was it tested in dogs at all (a question a lot of animal welfare organisations have raised)? And why is it being reported in an animal health blog?! In this blog, I’m hoping to answer all these questions, and explain why this is such an important breakthrough.


What is Muscular Dystrophy?

Although there are several types of the disease, one of the most severe is Duchenne Muscular Dystrophy, or DMD. This is a disease where a mutation (an abnormal DNA code sequence in a gene) occurs in the gene that produces a protein called “dystrophin”. The dystrophin protein helps to anchor the “pulling proteins” in a muscle cell to the cell membranes; without it, every time the muscle contracts, more and more damage is done to the cell. Eventually, the cell dies; over time, the patient’s muscles become weaker and weaker. Most human sufferers need a wheelchair by their early teens, and even with treatment rarely live beyond their early thirties, eventually going into heart failure (as the heart muscle is affected) or respiratory failure (as the muscles for breathing gradually fail).


Who suffers from it?

DMD is the most common form of muscular dystrophy, and each year in the UK alone about 100 babies are born with the condition. Almost all the sufferers are boys, because the gene is present on the X chromosome – girls have two X chromosomes, so have 2 copies of the dystrophin gene. If one is damaged, it doesn’t matter, because the other one acts as a “backup” and makes the protein instead – although they can pass it on to their children. Boys, however, have only one X and a Y chromosome, so only have one copy of the gene. If that is damaged, they will inevitably develop the fatal and (currently) incurable disease.


Hang on, this is all about humans… where do animals come in?

Because dogs can suffer from the same condition. It’s rare – only 1 in 12,000 dogs are reported as suffering from muscular dystrophy – but when it occurs, the mutation is very similar to one that occurs in people with DMD.

This was recognised some years ago by the vets at the Royal Veterinary College (The RVC, also known, rather inaccurately, as London Vet School). They have a group of dogs who are all descended from that first affected dog, and are therefore suitable for research like this. As a result, the research being done at the RVC and their partner institution (UT Southwestern (UTSW) Medical Center in the USA) will help both people and dogs with this devastating disease.


Is it ethical to use these dogs for experiments?

It’s worth bearing in mind that this disease exists naturally (it hasn’t been genetically engineered), and the dogs in question are kept in the best possible conditions, and when the affected individuals develop symptoms they have access to genuinely state of the art veterinary care (although I’m not an RVC graduate, I have to admit that they are second to none). When the symptoms are too severe, they are put to sleep before they can suffer, and the whole programme is overseen by an independent ethics board. You can read about the programme and how well the dogs are looked after here.

In this case, the experiment is a trial treatment of the disease – it’s been tested in vitro (in the lab on cell cultures) and it worked there; it’s been tested in mice and it worked there – however, the mutation was artificial in that experiment, and additionally mice do not express the disease in the same way that dogs (or children) do. This is, therefore, the next logical step.

I appreciate there are those who believe that animals should never be used for research, and I do respect that point of view. It is not, however, one that I share; in this case, for a disease that is apparently identical in both dogs and humans, a treatment for dogs is being tested on dogs, which may eventually help treat people. Ultimately, it’s win/win – the dogs that were in the experiment were doomed from birth, this way, they have potentially helped to save their littermates’ offspring, plus countless thousands of other humans and dogs.


How does it work?

This is the really clever bit. Previous gene therapies have focussed on replacing a faulty gene with a healthy copy; however, the dystrophin gene is too big for that to work.

However, the most common form of DMD is a mutation that makes a part of the gene called exon-51 unreadable – which is the mutation that the dogs at the RVC have (and is responsible for 13% of cases in children). With an unreadable exon-51, the body cannot manufacture the healthy protein (it’s called a “frame-shift mutation”, and you can read more about it here).

Ironically, if it cannot be read, exon-51 becomes the problem. The research team used a procedure called crispr-cas9 (a sort of “genetic scissors”) to cut exon-51; with that gone, the cell’s natural repair mechanisms kicked in, resulting in production of a shorter, but functional, dystrophin protein.

The crispr “scissors” were introduced into the body using an adenovirus – a virus that is harmless to the patient, but can transport the treatment into the cells.


OK, but does it work?

Yes! After a single injection, the levels of dystrophin produced were dramatically increased – in one dog, up to 92% of normal in the heart muscle, although the others showed slightly lower effects. Overall, a boost of 15% is thought to be needed to have a significant effect, if given before symptoms appear, and most of the treated dogs easily exceeded that level. Even the poorest response produced 3 times more dystrophin than the most effective licensed therapy available.


So is this a cure?

Possibly – but with follow-up only 6-8 weeks after treatment so far, it’s possible that the effect will not be as long-lasting as we all hope. While the initial indications are really, really good, we also don’t know for certain whether the increased amount of dystrophin will delay the onset of symptoms, or make the symptoms milder – it should, but we’re not sure yet! In addition, there’s the possibility of side effects that needs to be investigated. Unfortunately, all the treated dogs had to be put to sleep in order to gather the information the researchers needed – hopefully, now we know that it works on the cellular level, the next study can follow dogs as they grow up following the treatment.


Is the hype justified?

Definitely – if this works, it means that the dogs, and thousands of affected boys worldwide each year, can go on to live a normal life… and that the other forms of muscular dystrophy are potentially treatable too!


Want to know more?

The RVC’s report is here, and there’s a good article on DMD itself from the NHS. There’s also a good news article (with some lovely quotes!) from Healthday, and another from the Guardian.

The editorial article in Science is here.