Degenerative diseases are never a fun topic to talk about. They involve the gradual wasting away of the body or mind, the losing of oneself over time to decay. History has long focused on such disorders and the horrors both for the person and those around them. It is no surprise then, that with the advent of gene therapy technologies, it is diseases like this that were the first to begin being investigated thoroughly.

An Ongoing Topic

Progress since then has continued steadily, with more and more steps toward an outright cure being made and palliative treatments being discovered along the way. Today, we’ll be focusing on Duchenne muscular dystrophy (DMD), a famous one that was one of the expected first breakthroughs when CRISPR came onto the scene. But CRISPR isn’t involved this time.

We’ve discussed this topic before, focusing then on how to help people already in middling or late stages of the disorder. But that article did not have a method to outright cure (or at least have a treatment capable of mitigating the effects for years at a time) DMD. Now, thanks to an experiment on dogs, we might have just that and a comparative animal model to boot.

A Background on DMD

Let’s discuss DMD first though. Duchenne muscular dystrophy is a genetic disease linked to the X chromosome. Due to this, it only affects men or those with a single X chromosome with a rate of about 1 in 5,000. It is a single gene disorder, where only one gene has been mutated out of its normal function and thus results in the condition. The gene causing DMD normally produces the protein dystrophin, responsible for stabilizing the cytoskeleton of muscular cells throughout the body.

Without this protein, DMD patients are unable to work their muscles properly, meaning their muscles do not get stronger and slowly deteriorate over time. This worses throughout childhood and usually results in being wheelchair bound by the early teens. By the late teens and 20’s, this can increase to an inability to work the chest muscles properly to breathe and cardiac muscles being unable to keep the heart pumping. Thanks to this, even with modern medical technology, almost all DMD sufferers die by their 40’s.

Viral Vectors And Microsizing Genes

Hopefully we may soon be able to change that. Researchers from France and the UK conducted a gene therapy and transfer experiment on dogs affected with the disease. The medium of choice was recombinant adeno-associated virus (rAAV) vectors, which have had the DNA coding for dystrophin recombined into their viral genome so that the viruses will transmit it into the host cells.

But, of course, it’s not that simple. The actual full gene coding for dystrophin production is around 14 kilobases long, far longer than would fit within the viral capsid. Alternatives were made in the past that were shortened versions of the gene and protein, called microdystrophins. These contain the most vital parts of the dystrophin gene and were thought up when it was found that people with another form of the disease called Becker muscular dystrophy had far milder symptoms when more deletions or mutations were made to their already damaged gene.

This is thanks to the dystrophin proteins being modularly active and able to at least partially do their work so long as they have certain parts of the overall gene. So the entire gene may not be needed to at least reduce the effects of the disorder. A specially designed variant called MD1 was used with the viral vectors and injected into the intramuscular tissues of golden retrievers with DMD, along with it being spread throughout their other muscular and skeletal tissues. Unlike past experiments, this was done without any sort of immunosuppression.

Good Boy, Best Experiment

The study used 12 golden retrievers as the experimental group and all of them were ensured to be at a young enough age not to be exhibiting any muscular deterioration yet, which could foul up the results. After two years of following the dogs, as of the publication of the study, they found significant and sustained improvement in their muscular functionality. They were able to walk with a normal gait and did not show any signs of negative immune system response to the viral exposure, with the virus remaining at working levels in the muscles of the body without any issues.

Two years is still too short for the researchers to definitively say that cardiac issues had been resolved from the treatment, since that is usually one of the very last symptoms late in onset of the disorder, but they have some confidence that it has been avoided.

Having a canine model to compare gene therapy results such as this is highly important, because canine immune systems and muscular development is very similar to that of humans and is directly comparable to what the outcome of the treatment would be for human patients.

On To Human Trials

With this result, especially without needing any immunosuppressants so long as the treatment is given at a young enough age to avoid immune system development, it gives a great boost toward approving a human trial and eventually widespread usage of the treatment method. Combined with other research endeavors involving genetic repair using CRISPR and similar tools, a cure for DMD and other degenerative disorders may be sooner than we think.

Press Article Link

Study Link

Photo CCs: Golden Retriever 10weeks from Wikimedia Commons

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