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The Controversial Gene Therapy for Duchenne Muscular Dystrophy

Stuck with a defective gene? We can patch it up, but at what price and will it even work?

As medicine uses more and more complex tools to treat illness, I worry that these newer interventions will be seen as impenetrable black boxes. A pill is easy to understand, but gene therapy?

There is a simple story to tell about gene therapy. Your body has a defective gene. Doctors will give you the correct version of the gene and the disease will go away. It’s like being unhappy with your wall colour and simply painting it over with a fresh coat of paint. Suddenly it’s new and functional.

The reality, I’m afraid to report, is a lot more complicated. Gene therapy is very promising, but the devil hides in the details. The Food and Drug Administration in the United States just approved a gene therapy for Duchenne muscular dystrophy, and though it sounds like a homerun, doubt still lingers.

The longest gene in the genome

Duchenne muscular dystrophy is no walk in the park. It was originally described by the English physician Edward Meryon and later characterized by his contemporary, the French neurologist Guillaume Duchenne de Boulogne, hence the name. It affects almost exclusively men, for reasons that will become clear. The disease expresses itself as a progressive muscle degeneration. It becomes apparent around the ages of 2 to 4 and leads to the use of a wheelchair by 12 and assisted ventilation right after puberty. Modern medical care has allowed people with Duchenne to often live into their thirties, even forties, but eventually the heart and lungs fail.

While some diseases like asthma have very complex causes, with over a hundred genes and many environmental factors playing a role, Duchenne muscular dystrophy (DMD) is what is known as a Mendelian disease. One gene has a defect, and this gene codes for a protein, which is thus compromised, and this broken protein results in the disease. It’s like trying to build a proper house when the architectural plan has a glaring mistake in it.

In the case of DMD, the defective gene happens to be the longest gene in the human genome. It spans a whopping two million bases—that is two million As and Ts and Cs and Gs arranged in a particular pattern to spell out the instructions to build a giant protein called dystrophin. You can think of dystrophin as an integral part of a springy scaffold that links our muscle fibres to their immediate surroundings. In DMD, the dystrophin the body produces is wrong. Often, it is missing a large chunk, so the scaffold is compromised. Although we are not sure exactly what happens at the molecular level that results in this progressive muscle degeneration, the leading theory is that muscles become damaged during contraction and over time this damage triggers inflammation, which prevents the muscle fibres from regenerating. Slowly but surely, muscle mass becomes replaced by fat and fibrous tissue. The heart muscle likewise gets compromised, and death follows.

Why are (almost) only boys affected? It turns out that the dystrophin gene is on of the X chromosome. Males only have one copy of this sex chromosome, so a single, devastating mutation in the dystrophin gene leads to disease. Females, however, have two copies of the gene and can often rely on the second, unaffected copy as a backup to produce a healthy protein. Through rare genetic events or the sheer bad luck of having two mutated copies of dystrophin, fewer than one in a million women end up with DMD, while the rate is much higher in men: one in 3,500 to 5,000.

There is no cure for DMD and the main drug treatment is steroids. They slow the progression of the disease down seemingly by reducing the inflammation and allowing some muscle regeneration. But steroid use, either daily or intermittent, comes with a high price: weight gain, increased risk of fractures, and a long list of neurological, digestive, and metabolic issues.

Steroids don’t alter the root cause of the disease. For that, we would need to fix the gene that codes for dystrophin, either by editing it the way we can with text on a computer or by giving each muscle cell a clean version of the gene.

Believe it or not, this is already happening.

Honey, I Shrunk Dystrophin

Gene therapy is the use of a gene to treat or prevent a disease. A few of these therapies have been approved in some countries, with many being used to treat certain cancers. It sounds simple enough: stick your gene of interest inside of a tiny vehicle, often the shell of a virus, and inject it into the patient. The gene will produce the protein of interest and voilà! Problem solved. There are, however, several hurdles, and the race to treat DMD with gene therapy displays all of them.

For example, these hollowed-out viruses are known as viral vectors, and most of them simply do not target muscle cells. As we saw with COVID-19, viruses have a tropism. Like daisies turning toward the sun, a virus will be drawn to certain cells in the body because of the receptors these cells display at their surface. COVID-19’s coronavirus is drawn to cells expressing the ACE2 receptor, and a virus called AAV is attracted to muscle cells, which makes it the viral vector of choice for treating Duchenne muscular dystrophy.

Remember how dystrophin is the longest gene in our genome? This may elicit a write-up in nature’s book of world records, but it poses a real challenge when scientists want to stuff this colossal piece of DNA inside of a virus. It simply will not fit.

If we take the dystrophin gene’s epic two million bases and trim them down to the minimum needed to encode the full protein, we still get a molecule that is two and a half times bigger than what AAV can carry. Solving this problem required looking at the clinical landscape. There is another form of muscular dystrophy caused by mutations in the dystrophin gene, but it is much milder. Inspired by the smaller yet still somewhat functional protein seen in that disease, scientists created truncated versions of dystrophin called mini-dystrophin and micro-dystrophin that they could slip inside the viral vector. The hope is that, though they are even smaller than what is seen with that milder form of dystrophy, they would be functional enough. A person with DMD would thus trade a serious disease for a milder one.

But managing to zip up the suitcase of the viral vector is only one of the challenges. We have hundreds of muscles, which form 30 to 40% of our body mass, and all of these muscles need to incorporate the virus and its payload. Access is made harder by the layers of connective tissue that surround our muscles. And this type of therapy, if it works, cannot restore the muscle tissue already lost, so it has to be delivered when the patient is still a young child. Yet, the patient’s own immune system can easily get in the way. The AAV vector is a modified incarnation of a type of virus that naturally and commonly infects humans, so many of us have developed antibodies against it. DMD patients who already have antibodies against AAV are not eligible for this type of gene therapy, and for those who are eligible, there’s a kicker: they will develop antibodies against AAV during treatment, which means they cannot get a repeat treatment or any other gene therapy in the future which would use this viral vector. Eventually, using different variations of AAV might bypass this immune response, but for now, patients interested in trying gene therapy have to make a consequential decision: do I try the first one approved or wait in the hope that future versions might be better? They might only get one shot.

Gene therapy for DMD, as magnificent as it sounds on its surface, is thus a much pricklier animal. It can cause health problems not seen in laboratory mouse models, because their immune system is too different from ours; its longevity is unclear since muscles eventually turn over, taking with them the healthy dystrophin gene they had incorporated; and it is expensive and work intensive. The pharmaceutical process currently takes a month or two per patient, whereas 400 new patients are born each year with DMD in the United States alone.

Are these gene therapies for Duchenne muscular dystrophy ready for primetime?

To approve or not to approve

The Food and Drug Administration recently had to decide whether or not to approve a gene therapy for DMD formerly called SRP-9001, now rechristened Elevidys. (Its full name, sounding like a Harry Potter spell, is “delandistrogene moxeparvovec-rokl.”) The phase III clinical trial testing it against placebo is not over, yet its manufacturer, Sarepta Therapeutics, was asking for fast-track approval. During a committee meeting last May, a number of issues were raised.

The manufacturing process for the viral vector and its micro-dystrophin gene had recently changed significantly, which meant that the injection contained more empty viral vectors than before. There was a reliance on mouse data, even though mice with DMD do not represent humans very well. It was still unclear if the micro-dystrophin gene would produce a protein that worked well enough. The main result from the on-going clinical trial is a series of tests, such as walking, standing up from a chair, and rising from the floor, which is easy to influence through coaching and motivation. The disease itself is very variable in infancy, so disentangling the effect of the treatment and that of normal variation is not easy. And there are safety concerns. The committee’s conclusion at the time? “Patients likely have only one chance to receive an AAV vector-based gene therapy for DMD,” so it is “critical that it is effective and safe.” The price tag on Elevidys was recently predicted to be USD 2 million.

On June 22nd, the FDA approved the therapy for patients aged 4 to 5 years old who do not already have antibodies against AAV, pointing out that a clinical benefit (such as better motor function) had not been established. We will have to wait for the phase III trial to be done to know if this version of micro-dystrophin really works.

Gene therapy as a concept is sound. The difficulties lie in its technical application, but there is no shortage of innovative solutions. Already, one researcher devised a system to carry the full dystrophin gene as separate pieces in different AAV vectors, which could then assemble, Voltron-style, inside the muscle cell. Others are exploring different types of vectors, such as antibodies and tiny fat droplets.

Sticking a healthy gene inside a cell is one way to go, but some are focusing their efforts on using the gene editing machinery of CRISPR to edit the mutation out of the dystrophin gene inside the patient’s own cells, while others are building personalized bits of DNA that will bind to the dystrophin gene and allow the proper protein to be built by forcing the cell’s machinery to skip the bad part.

Applications of this latter technology have already been approved for DMD in some countries, but there too we see evidence of expensive drugs being approved based on underwhelming data. The medication eteplirsen (trade name: Exondys 51) is one such example. The FDA approved it not because it was shown to improve patients’ muscle strength and function, but because some amount of healthy dystrophin protein could be detected in these patients. Faced with the same indirect evidence of benefit, Europe’s agency did not approve the medication.

I do believe that gene therapy will revolutionize medicine, and I am deeply sympathetic to patients and their loved ones who are desperate for a solution, but these kinds of approvals are making me uncomfortable. The price tag is sky-scrapingly high and the benefits are up in the air. And in the case of Elevidys, there is one more important problem: you only get one shot at this.

Take-home message:
- Duchenne muscular dystrophy is a type of progressive muscle degeneration caused by a mutation in the longest gene in the human genome, dystrophin
- A gene therapy to treat this dystrophy has just been approved by the FDA in the United States, and it uses the shell of a virus to introduce a trimmed down version of dystrophin inside muscle cells
- There are many issues with this gene therapy, including the fact that it has yet to be shown that this smaller version of dystrophin does improve muscle function
- Patients who already have antibodies against the virus used for the therapy are not eligible for it, and patients who will use this therapy will develop these antibodies, making it impossible for them to receive a second dose or any other gene therapy using this virus unless the technology changes in the future


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