Teaching cells to skip a genetic mistake

Children born with Duchenne muscular dystrophy (DMD) gradually lose the ability to walk, climb stairs and eventually breathe independently. The disease weakens muscles throughout the body, including those that power the heart and lungs. The condition mostly affects boys and is typically diagnosed in early childhood, when parents first notice that running, climbing or standing up from the floor becomes unexpectedly difficult.

“People with Duchenne destroy their muscle every day,” says Francesco Muntoni.

Each time a muscle contracts, tiny injuries appear in its fibres. In healthy muscle, these injuries are repaired. But without dystrophin – the protein missing in Duchenne muscular dystrophy – the damage accumulates more rapidly than the body can rebuild the tissue.

For decades, doctors could do little but watch the disease progress. Muntoni helped to pioneer an unusual strategy to fight it: Instead of trying to replace the enormous gene behind Duchenne, scientists learned how to make cells skip the faulty segment of the gene during processing.

A field on the brink of discovery

In the mid-1980s, the gene that causes Duchenne muscular dystrophy had not yet been identified. Doctors recognised the disease from its pattern of muscle weakness, but its genetic cause remained unknown.

When Francesco Muntoni first arrived in London during his training, the field was on the verge of a breakthrough.

Muntoni had trained in medicine and child neurology at the University of Cagliari in Sardinia, Italy. Two mentors shaped how he approached science: neuropharmacologist Gian Luigi Gessa and paediatrician-geneticist Antonio Cao.

“They were world-class scientists,” Muntoni recalls. “What impressed me most was their curiosity and rigour. They encouraged you to question things and to take the time needed to really understand a problem.”

From them, he adopted a principle that would guide his career: understand the mechanism behind a disease.

“What fascinated me most was understanding why the disease happens,” Muntoni says. “If you understand the mechanism, you can start thinking about how to change it.”

The moment scientists found the culprit

Francesco Muntoni joined the Dubowitz Neuromuscular Centre at Hammersmith Hospital – founded by the pioneering paediatrician Victor Dubowitz – where researchers were racing to identify the gene responsible for Duchenne muscular dystrophy and where muscle pathologist Caroline Sewry also worked.

“It was an incredible moment,” Muntoni recalls. “The lab was full of excitement because people felt that the gene was close to being found.”

In 1986, a team led by geneticist Louis Kunkel at Boston Children’s Hospital in the United States identified the culprit: the dystrophin gene. This discovery transformed the field. For the first time, scientists could study the disease at its genetic source.

The gene turned out to be extraordinary. With more than 2 million DNA letters and 79 exons, dystrophin is the largest gene in the human genome.

Its protein acts as a molecular shock absorber in muscle. Without it, fibres are damaged faster than the body can repair them.

A puzzle inside the dystrophin gene

The discovery of the dystrophin gene rapidly revealed a puzzle.

What became clear very quickly,” Muntoni recalls, “was that the gene was enormous and extremely complicated. Even more confusing was the variability: some patients had the severe Duchenne form, whereas others with mutations in the same gene had a much milder disease: Becker muscular dystrophy.”

Boys with Duchenne muscular dystrophy lose the ability to walk before their teens. People with Becker muscular dystrophy, by contrast, can remain mobile well into adulthood.

Understanding that difference became one of Muntoni’s earliest scientific obsessions.

As researchers mapped dystrophin mutations, a pattern emerged. Mutations that disrupted the gene’s reading frame caused severe Duchenne disease. Mutations that preserved the frame enabled cells to make a shorter dystrophin protein.

“That was the key insight,” Muntoni says. “If the reading frame was preserved, patients could still produce dystrophin and the disease was much milder.”

This distinction would later become the conceptual foundation for exon skipping.

A clue hidden in Becker muscular dystrophy

The genetic difference between Duchenne and Becker muscular dystrophy is small. The clinical difference is enormous. For Muntoni and others studying the disease, the contrast raised a crucial question: if both conditions arise from mutations in the same gene, why are their outcomes so different?

“The key lies in how the genetic message is read,” Muntoni explains.

Genes are typically built from segments called exons. When cells assemble the RNA blueprint for a protein, they join these segments together. But the genetic code is read three letters at a time - known as a codon. If that reading frame is disrupted, the message collapses.

If a single exon disrupts the reading frame, the entire protein can fail to form.

“It is like a sentence in which every word has three letters,” Muntoni says. “Remove only one letter and the rest becomes nonsense.”

When the genetic message breaks

In Duchenne muscular dystrophy, the mutation disrupts the gene’s reading frame, preventing cells from producing functional dystrophin.

“In Duchenne, the message becomes unreadable,” Muntoni says. “The cell tries to make the protein but encounters a scrambled instruction and stops.”

In Becker muscular dystrophy, however, mutations typically remove part of the gene without disturbing the reading frame. Cells can still produce a shorter dystrophin protein that retains much of its function.

“That observation was extremely important,” Muntoni recalls. “It showed that you do not necessarily need the full-length protein. Even a shorter dystrophin can still protect the muscle.”

In other words, nature had already performed the experiment.

Nature’s own experiment

Across laboratories studying dystrophin mutations, a clear pattern emerged. Mutations that disrupted the reading frame caused severe Duchenne disease, whereas mutations that preserved the reading frame produced the milder Becker form.

This observation suggested an unexpected possibility.

“If Duchenne is caused by a disrupted reading frame,” Muntoni says, “then in principle you might restore it and make the gene behave more like Becker.”

At the time, the idea was largely theoretical. The dystrophin gene was enormous, and the tools to manipulate RNA were only just emerging.

“But the principle was very attractive,” Muntoni says. “Instead of repairing the gene, perhaps you could change how the cell reads it.”

The idea of skipping a mutation

Experiments soon suggested that the reading frame might be restored.

Researchers discovered that short synthetic RNA molecules could bind to specific exons and alter how the cell assembles the final RNA message.

“By masking one exon you can force the cell to skip it,” Muntoni explains. “If you skip the right exon, the reading frame is restored.”

The effect was striking. Cells began producing a shortened but functional dystrophin protein.

“When we saw dystrophin coming back in the cultured muscle cells of children with Duchenne, it was very exciting,” Muntoni says. “This suggested that a severe Duchenne mutation could be converted into a milder, Becker-like mutation, rather than restoring normal dystrophin production.”

The challenge was turning the molecular trick into a therapy that could work in human muscle.

From molecular trick to medical experiment

Turning exon skipping from a clever molecular idea into a treatment for children was far from straightforward. In the early 2000s, the strategy still existed mainly in experimental models.

Researchers could demonstrate the principle in cells and mice, but no one had yet shown it could work safely for people.

Progress depended on collaboration across laboratories, including the establishment of a United Kingdom consortium. Some groups developed the antisense molecules that directed exon skipping, and others mapped which mutations might be treatable, while clinicians prepared the first trials.

“The mouse does not complain,” Muntoni says. “But when you move from mice to children, you must be absolutely sure that you do no harm.”

A molecule designed to rewrite the message

At the centre of the strategy was a short synthetic RNA molecule known as an antisense oligonucleotide (ASO). It binds to a specific exon in the dystrophin RNA message and hides it from the cellular machinery that assembles the final protein instruction.

“The concept is actually simple,” Muntoni explains. “You design a small piece of RNA that binds to a target sequence on an exon, masking it so the cell’s machinery does not read it. When the message is processed, that exon is skipped. If you skip the right exon, the reading frame is restored and the cell can produce a shorter but functional dystrophin.”

Turning that elegant logic into a therapy raised difficult questions.

“We were dealing with children who had never produced dystrophin,” Muntoni says. “Could the therapy trigger an immune response? Could it damage muscle? And would it reach enough cells to make a difference?”

The first experiment involving children

To answer these questions, Muntoni and colleagues designed one of the first human tests of exon skipping. The trial was deliberately small and cautious. A handful of boys with Duchenne muscular dystrophy received injections of the experimental drug into a single muscle in the foot, while the corresponding muscle in the other foot served as a control.

Weeks later researchers examined muscle biopsies.

What they saw had never been seen before. In untreated Duchenne muscle, fibres appear completely dark when stained for dystrophin. In treated muscle, some fibres show clear staining – evidence of newly produced dystrophin.

“When you examine Duchenne muscle, it appears completely dark under the microscope,” Muntoni recalls. “But when you start to see dystrophin staining coming back, even in small patches of fibres, that really makes your day.”

From a single muscle to the entire body

Equally important, the first experiment suggested that the therapy is safe.

“That was probably the most important result,” Muntoni says. “We could show that the molecule did not trigger inflammation or immune rejection in the muscle.”

The strategy that had worked in animals now appeared capable of working for children. But another challenge remained. Injecting a single muscle could prove the concept, but Duchenne muscular dystrophy affects the entire body.

“If this was going to become a real therapy,” Muntoni says, “it had to reach all the muscles.”

Delivering exon skipping molecules through the bloodstream therefore became the decisive test. Muscles make up about 40% of the body, so any therapy would have to reach an enormous number of cells to matter clinically.

Muntoni and colleagues designed a second trial in which the therapy was delivered intravenously so it could circulate throughout the body.

“That was the real test,” Muntoni recalls. “Treating a single muscle could show the concept, but Duchenne affects the entire body.”

Similar to the earlier experiment, the study proceeded cautiously, with doses increased step by step while researchers monitored safety.

“The first question was always safety,” he says.

When dystrophin finally returned

At first, the results were discouraging. At low doses, the biopsies showed almost no change.

“At the beginning, the signal was very small,” Muntoni recalls. “We worried that the molecule was not reaching enough muscle cells.”

But when the dose increased, the picture changed. Dystrophin began to reappear in muscle fibres.

“When the dose-escalation part of the study reached the higher dose levels, we started to see dystrophin coming back,” Muntoni says. “Not at normal levels, but clearly there. That was the moment we realised that the strategy could work for patients.”

For the first time, scientists showed that a genetic therapy could restore dystrophin in individuals with Duchenne muscular dystrophy using a safe and well-tolerated drug.

The levels were modest – with the three best responders showing newly formed dystrophin in 15–55% of muscle fibres by immunohistochemistry, a method that uses staining to detect dystrophin in muscle tissue and the primary readout at the time – but biologically meaningful.

“Even small amounts of dystrophin can make a big difference,” Muntoni says.

From experiment to approved therapy

The findings provided the first proof that exon skipping could work for humans and opened the door to larger clinical trials. Within a decade, the first exon skipping therapy targeting exon 51 of the dystrophin gene received accelerated approval from the United States Food and Drug

Administration, followed by a second therapy targeting exon 53, also developed by Muntoni’s team.

“These drugs are not a cure,” Muntoni says. “They must be given repeatedly, and each works only for patients whose mutation can be corrected by skipping that specific exon. But they show that it is possible to modify the genetic message and restore dystrophin among patients.”

The strategy also introduced a new form of precision medicine, in which therapies are designed for specific mutations within a single gene.

“What Duchenne taught us,” Muntoni says, “is that you do not always have to replace the gene. Sometimes you can repair how the cell reads the message.”

From one disease to a platform

Once exon skipping proved possible in Duchenne muscular dystrophy, its implications quickly extended beyond a single disease. The strategy revealed something fundamental about genetic medicine: sometimes disease can be changed not by replacing a gene but by changing how the cell reads it.

The same principle applies to many genes, where segments are assembled into RNA instructions for proteins. If the reading frame can be restored – even when parts of a gene are missing – cells may still produce a protein that works.

“Genes are not rigid structures,” Muntoni says. “Even an imperfect protein can sometimes function well enough to change the course of disease.”

Researchers soon began applying antisense strategies to other genetic disorders. One striking example is spinal muscular atrophy, in which an antisense drug modifies gene splicing so that cells produce more of a critical survival protein. The therapy has since become one of the most successful RNA medicines in clinical practice.

“The Duchenne field helped show that antisense molecules could work for patients,” Muntoni says. “Once that principle was established, researchers began asking whether the same idea could apply to other genetic diseases.”

Today antisense therapies are being explored for metabolic, neurological and other neuromuscular disorders – all built on the same principle: instead of rewriting DNA, they reshape the RNA message.

“Rare diseases are often where new therapeutic ideas are first tested,” Muntoni says.

Why the first exon skipping drugs are only the beginning

The success of exon skipping has also revealed the limits of early RNA therapies. First-generation drugs restore only modest amounts of dystrophin, and their effects vary between patients.

“We are still learning why these therapies behave differently in human muscle than in animal models,” Muntoni says. “Biological barriers that are only now beginning to be understood limit how much dystrophin we can restore.”

More than 10 companies are now developing improved exon skipping drugs for Duchenne, each aiming to restore higher levels of dystrophin using different strategies.

“Competition is actually a good sign,” Muntoni says. “It shows that the field has matured and that many groups believe that the strategy can be improved.”

But competition also raises another challenge: managing expectations.

“Because these are genetic diseases, people often assume that the therapy will be a cure,” he says.

“In reality, progress is gradual. We are learning step by step how much dystrophin is needed and how much improvement is possible.”

Balancing hope, safety and scientific reality

Few areas of medicine carry as much emotional weight as severe genetic disease affecting children. Families come to the clinic hoping for breakthroughs, and rapid scientific advances can make those hopes feel almost real. But biology rarely moves as fast as expectations.
Muntoni has spent much of his career navigating that tension.

“In rare genetic diseases, expectations are understandably very high,” he says. “Families hope that science will move quickly. But biology does not move at the same pace as hope.”

From the beginning, he approached exon skipping trials with a simple principle of medical ethics: primum non nocere – first, do no harm.

“At first, we were simply asking whether the biology worked,” Muntoni recalls. “Only later could we ask whether those changes would translate into clinical benefit.”

“There is often an expectation that one discovery will suddenly cure the disease,” he adds. “In reality, progress usually comes step by step.”

“For this condition, these therapies will not be a complete cure,” Muntoni says. “But you need to start where there is nothing.”

Longer lives reveal a new side of the disease

Thirty years ago, many boys with Duchenne muscular dystrophy did not live beyond adolescence. Advances in respiratory and cardiac care have since extended life expectancy dramatically, enabling many people to live well into adulthood.

“That change alone shows how much difference incremental progress can make,” Muntoni says.

As patients live longer, researchers are uncovering new aspects of the disease. One surprising discovery is that dystrophin is not only important in muscle.

“Dystrophin is not just a muscle protein,” Muntoni explains. “Forms of it are expressed in the brain and seem to play a role in neural signalling.”

This well explains why around 40% of boys with Duchenne muscular dystrophy experience learning difficulties or features of attention deficit or autism spectrum disorder.

“We are now seeing patients living longer lives,” Muntoni says. “That means we must understand the neurological aspects of the disease much better so that patients have the optimal possibility to participate in life.”

Muntoni’s group and others are therefore exploring whether exon skipping strategies used to restore dystrophin in muscle might one day also work in the brain.

“If so, exon skipping might one day address not only muscle weakness but other features of the disease as well.”

Francesco Muntoni

The long road of genetic medicine

From the outside, the history of Duchenne muscular dystrophy research can look like a rapid revolution. In reality, it has been a slow accumulation of insights – each step revealing both progress and new biological complexity.

Muntoni has lived through nearly every stage of that transformation.
When he began working in the field in the 1980s, researchers did not yet know which gene caused the disease. The discovery of the dystrophin gene changed that, but it also revealed the scale of the challenge: a vast gene, many different mutations, and the daunting task of repairing a genetic disease.

“Back then we did not even know which gene was responsible,” Muntoni recalls.

“Once dystrophin was discovered, it opened a completely new way of thinking – but also showed how complex the biology really was.”

From gene discovery to RNA therapy

Four decades later, the landscape looks very different. RNA-based therapies are now approved or in development, companies are racing to improve exon skipping drugs and gene therapies are being tested alongside new delivery technologies.

For Muntoni, the most important shift is conceptual.

“For many years, the dominant idea was that you had to replace a faulty gene,” he says. “Duchenne showed that sometimes you can achieve something similar by changing how the genetic message is read.”

This insight – repairing the message rather than replacing the gene – has helped to shape the emerging field of RNA therapeutics.

Even so, Muntoni remains cautious about the language of breakthroughs.

“In medicine, there is often a temptation to describe every advance as a revolution,” he says. “But most progress happens step by step.”

“Even small amounts of dystrophin can make a big difference, and this is an important step,” he adds.

Why progress in medicine comes step by step

Children who once faced rapid muscle deterioration can now retain strength longer, remain independent for more years and increasingly live well into adulthood. For families who once had no treatment options, even partial biological corrections can reshape expectations for the future.

This long arc of progress – from gene discovery to molecular therapy – is what the Novo Nordisk Foundation recognised in awarding Francesco Muntoni the 2026 Novo Nordisk Prize.

For Muntoni, however, the story is far from finished. The biology of dystrophin continues to reveal new layers: from its role in the brain to the mechanisms that limit current therapies.

“I do not like magic,” he says with a smile. “People often talk about new technologies as if they will suddenly solve everything. But without deep understanding of the biology, putting new developments into context is difficult.”

“And real progress,” he adds, “comes from uncovering it patiently.”