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“A Second Chance at Life”: Can Gene Therapies Beat Rare Disease?

A child jumps under a skipping rope held by their parents.
Credit: Technology Networks
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Around the time that Connie Elson turned five, her memory and concentration started slipping. Connie’s parents took her for a private auditory test, suspecting that she was struggling to hear. But over the next year, Connie began to have problems with her balance and had small absence seizures that her doctor suggested she would grow out of. Eventually, Connie’s mother Nicola and her husband Ian decided to take her out of school near their home in Cark, Cumbria, altogether. Nicola tells Technology Networks how she contacted Connie’s nursery teacher from a previous school to give an honest, professional opinion. “I still recall the nursery teacher's exact words when I collected Connie – ‘You need to get someone to have a really good, long look at her. This is not the same little girl that left nursery nine months ago,’” Nicola says.

The healthcare system began to spin into gear. Connie was referred for numerous tests, including a computed tomography (CT) scan, which uses X-rays to create detailed images of structures inside the body, including the brain. The crushing news came back: Connie was suffering from a degenerative brain condition.

How MLD affects the body

Connie’s doctors diagnosed her with a condition called metachromatic leukodystrophy (MLD), a rare, inherited disease. MLD begins in tiny cellular compartments called lysosomes. These are essentially the cell’s garbage disposals – waste components from the rest of the cell are sent to the lysosome to be broken down. But in MLD, which is part of a family of conditions called lysosomal storage disorders (LSDs), that breakdown process itself breaks down. This is because people with MLD lack a key protein, arylsulfatase A or ARSA, which is responsible for chopping up a class of molecules called sulfatides. Sulfatides are multifunctional lipids, with roles throughout the body including in insulin secretion and blood clot formation. In the brain and nervous system, sulfatides have particularly important jobs. Here, they regulate the formation of a fatty molecule called myelin.

Myelin protects our nerve cells and also acts as an electrical insulator for our brain signals. This enables their rapid transmission, which is essential for our bodies to function.

But in MLD, sulfatides become the body’s enemy. Without the ability to break them down, lysosomes start to overflow with sulfatides, which accumulate inside cells throughout the body. A sulfatide wave engulfs internal organs, such as the gallbladder. But the most damaging effect is on the brain. Sulfatides, usually the careful controllers of myelin, now spread unchecked through this protective coating, destroying it. Without myelin, brain signaling begins to break down, affecting movement and cognition. This damage is seen in other brain diseases – some cases of MLD have even been misdiagnosed as multiple sclerosis (MS) – but unlike MS pathology, in MLD the degeneration is very rapid and invariably fatal.

While MLD alone only affects roughly 1 in 100,000 people worldwide, “rare” conditions affect roughly 5% of the world’s population. 

There are several different subtypes of MLD. The exact subtype that patients develop appears to be based on the types of mutations present in their ARSA genes. For some children, enough residual enzyme activity is present for them to stay healthy until adulthood. For others, symptoms manifest between the ages of 3 and 16. The most severe form of the condition has an onset in infancy.

MLD is an autosomal recessive condition. This means that it can be inherited from completely unaffected parents. After Connie’s diagnosis, her younger brother Joe was also tested for mutations in the gene (also named ARSA) that codes for ARSA. The results came back with the devastating conclusion that Joe, outwardly a healthy toddler, also had mutations that would ultimately lead to MLD.

A gene therapy provides hope

This is a story that many families with so-called “rare” diseases face. While MLD alone only affects roughly 1 in 100,000 people worldwide, “rare” conditions affect roughly 5% of the world’s population. Of these conditions, 72% are genetic and 70% have a childhood onset.

A woman in a lab coat holds the hand of a young boy. Dr. Francesca Fumagalli with a child involved in the clinical trial. Credit: San Raffaele Telethon Institute For Gene Therapy/Dr. Francesca Fumagalli.

LSDs are some of the most starkly cruel conditions humans can ever face. Other examples include Fabry disease, which can damage the kidneys and cause bouts of burning full-body pain, and Niemann–Pick disease, type C, which produces a rapid childhood dementia. These are awful, incurable diseases.

But around the time that Connie and Joe were diagnosed, the grim prognosis for MLD patients was rapidly changing. Through an extensive online search, their parents discovered that a clinical trial had started up to develop a therapy for MLD, 800 miles away in Milan. The trial was based in the city’s San Raffaele Hospital, led by a team including Dr. Francesca Fumagalli.

The treatment that Fumagalli helped develop at the hospital's San Raffaele Telethon Institute for Gene Therapy, atidarsagene autotemcel (dubbed arsa-cel), is an ingenious and innovative gene therapy.

How arsa-cel works

In arsa-cel, Fumagalli tells Technology Networks, hematopoietic stem cells (HSCs) that reside in the children’s bone marrow are extracted and genetically modified. Previously unable to produce ARSA, post-treatment these cells are filled to the brim with the enzyme. Once reinfused into the patient’s bloodstream, the new cells travel throughout the body, Fumagalli says. “MLD is a disease that involves the central and peripheral nervous system. The new cells enter the brain where they give rise to a population of resident microglial cells that can deliver the enzyme to the surrounding cells.” This includes cells that give rise to the myelin sheath, meaning that toxic sulfatides are chopped to pieces and rendered harmless.

What is gene therapy? 

Gene therapies introduce specific DNA sequences into a patient’s body to address the symptoms of a disease, prevent or cure it. The genetic change may involve a functional gene being added to replace a missing or non-functional one. Other therapies include using sequences of nucleic acids to modify how genes are expressed in the body. The field is increasingly using genome-editing technologies that change cellular DNA at targeted locations to treat disease. 

That simple summary belies an incredibly involved process, both in the lab and clinic. One major challenge for patients is that the immune system must become a clean slate to make sure that enough modified cells make it through to the brain. “We need to restore the entire hematopoietic stem cell system,” explains Fumagalli. To enable this, a radical program of chemotherapy is used to erase the patient’s HSCs. The new, beefed-up HSCs are then infused, but patients then must endure a wait time during which they are in a state called aplasia, where they have vastly impaired immune function. “The child has to stay in a sterile room for some weeks waiting for them to recover before they can go home and back to a normal life,” says Fumagalli.

When Nicola and her family became aware of arsa-cel, it remained in an early clinical trial phase. Like many such trials where the drug’s disease-combating ability is what makes or breaks the compound, strict eligibility criteria determined who would be able to access the treatment. While Joe, still in a pre-symptomatic stage, was eligible, Connie’s symptoms had advanced too far during the preceding year and she was no longer well enough to take part in the trial.

A transformative impact

Nicola and her family began an onerous voyage to a foreign country, with their two vulnerable children in tow. Joe and the other children on the trial had to tolerate the side effects of the chemotherapy they were given, such as hair loss and mottled skin. But the benefits of the gene therapy itself were significant and enduring. A paper that Fumagalli and her colleagues published in The Lancet compared how the children in trial progressed against a group of historical case studies from before arsa-cel was developed. At a cellular level, the treatment dramatically fired up ARSA. Compared to untreated cases, patients with the most severe infantile-onset form of MLD showed an 18.7-fold increase in enzyme activity.

That increase had a transformative impact.

The trial had to hit a target of improving overall motor function by 10% to show that arsa-cel was really helping patients’ symptoms. The therapy blew that figure away. Two years after treatment, children with later-onset MLD showed improvements of 42% compared to those who were unable to access the therapy, while the figure for participants who would have been most severely affected by the infantile variant was 66%. A year after these measurements, treated children maintained their levels of motor function, which would have further declined without arsa-cel.

Many clinical trials for stubborn and poorly understood conditions – like Alzheimer’s disease – output underwhelming data. Such results kick off a squabble between biotech companies and regulators over statistical significances and fractional improvements that produce nearly non-existent changes to patients’ lives. With arsa-cel, the effect of the treatment could not be more obvious. For every factor analyzed, untreated children experience a rapid decline that does not recover. The same metrics show an almost unimpeded development for children given the therapy.

Dr. Francesca Fumagalli with a trial participant. Credit: San Raffaele Telethon Institute For Gene Therapy/Dr. Francesca Fumagalli.

Arsa-cel was an incredible success – a white whale in treating rare diseases. It would go on to be licensed as a commercial gene therapy called Libmeldy® that was approved for use in the European Union in 2020. The campaign to prove that MLD could be treated had been won, but getting that treatment to patients would prove far from straightforward.

A rollercoaster to approval

Libmeldy comes with a substantial price tag – roughly £2.8 million per dose. That cost reflects the therapy’s small patient base, one-time usage and incredible efficacy. It was now down to individual regulators to decide whether they could offer subsidies to enable MLD patients to access the treatment. In 2021, the UK’s drug regulator – the National Institute for Health and Care Excellence (NICE) – rejected Libmeldy on first consideration, citing its high cost and lack of long-term efficacy data. Individual families might be demoralized by such a decision. That’s where having cool heads on your side that understand the complex nature of how regulators approach these decisions is a major benefit.

One such cool head is attached to the shoulders of Sophie Thomas, senior head of patient services and clinical liaisons at the Society for Mucopolysaccharide and Related Diseases (MPS). Thomas works with families affected by a range of rare diseases, including MLD.

Thomas has worked for the MPS Society for over 20 years and is acutely aware of how treatments can be put through an arduous process by NICE, which has the exceedingly not-nice job of deciding which drugs and therapies can be accessed by vulnerable patients for free on the UK’s National Health Service (NHS). “History seems to dictate that NICE always gives a negative decision the first time around due to the level of uncertainty and need for further discussion and evidence,” says Thomas. “It's what happens after that which is the crucial point.”

With her team and other patient groups, Thomas put together an advocacy paper that drew on patient and family experiences of Libmeldy from around the world. The resulting document attests to the therapy’s life-changing efficacy. Detailed follow-up statements were obtained concerning 13 patients who had received Libmeldy several years previously. In five patients who were fully treated with Libmeldy before symptoms emerged, there was no progression of symptoms. Another five who progressed during the treatment saw their symptoms stabilize. One child failed to stabilize after symptoms had progressed and another two had disease progression after treatment, although this was limited to motor rather than cognitive effects.

The white paper’s unique value was in detailing how the treatment benefited the children's lives qualitatively, rather than just on a clinical scale. Treated children were able to take horse riding classes, go biking, play basketball and football, create games on Roblox and generally share the activities that their peers did. The treatment didn’t just benefit the children, but their families as well. One mother who contributed to the white paper wrote that she was able to be “100% Mum. Not 20% nurse, 20% admin, 20% voice for my child to get what they need, 10% dietician, 10% physio, 10% OT, 5% counselor to the rest of the family and what little is left as Mum.”

The whitepaper, alongside a catalog of other advocacy statements and evidence from fellow stakeholders, was submitted to NICE. In February 2022, Libmeldy was approved at the second time of asking, meaning affected families would have to pay nothing to access this transformative treatment. For Thomas, it was a huge vindication. Among the wider patient population, she says, “there was sheer elation. There were families that felt it gave hope for the future. That the treatment had not only saved their child's life but, as parent–carers, they had been given their life back. They had a chance to live along with their child, and now other children would have a chance to live too.”

Screening challenges

With heroic advocacy from many patients, scientists and charities, MLD patients in the UK now finally have a drug that can treat the condition. But Connie and Joe’s story shows that an effective treatment is just half the battle. For many rare genetic conditions, treatment must be delivered early to be a success.

In the UK, every newborn is screened for a range of potential metabolic conditions using a heel-prick test. This doesn’t involve genomic sequencing but instead looks for the presence of specific chemical markers that indicate the presence or absence of disease. For example, increased levels of immunoreactive trypsin are an indirect marker for the inherited disease cystic fibrosis.

Figure 1: In Europe and Central Asia, no country as rich as the UK screens for fewer newborn screening conditions in national and pilot programs except Luxembourg and the Republic of Ireland. Image credit: Technology Networks. Data Credit: World Bank/Loeber et al., 2021.

The nine conditions screened for in the UK are fewer than in Italy, Germany, Hungary, Estonia, North Macedonia and a host of other western countries (see Figure 1). But MLD is not on the list for any of the countries involved. The genetics of MLD are frustratingly complex and have complicated diagnostic test development. Surprisingly, up to two percent of the population may have a condition called ARSA pseudodeficiency, where levels of this key protein are extremely low, but no symptoms are produced. A metabolic test to detect the disease using a powerful technique called mass spectrometry was developed in 2016, although this has not been clinically approved.

Many other rare diseases are also absent from screening panels. Nick Meade, director of policy at Genetic Alliance UK, an umbrella group that represents people living with all forms of rare disease in the UK, says that this means affected groups must embark on a “diagnostic odyssey” to receive treatment. “It can take years to go from the point where you have your first symptoms of a rare condition to the point where you're in front of a specialist with them telling you the name of your condition,” says Meade. 

For many rare disease patients, he explains, there is a battle to just be believed by healthcare professionals. People from minority backgrounds or less formal education can struggle to be acknowledged by the system. “We found in a report that we published last February that young women are also struggling to persuade healthcare professionals that their illness was something that needed a diagnosis.” For children and young adults with MLD, their diagnostic odyssey needs to be as quick as possible. The UK National Screening Committee, which selects the tests that make it onto newborn screening panels, says Meade, prioritizes screening for conditions where “there is a direct gene to outcome relationship that's really strong and proven.”

For many rare disease patients there is a battle to just be believed by healthcare professionals.

That approach now looks out of step with other advanced healthcare systems, says Meade. “We feel as a community that the UK has fallen behind many other developed countries in how we're using newborn screening and that that process to approve new conditions onto that list for rare diseases in the UK is quite slow.” The National Screening Committee did not respond to a request for comment from Technology Networks.

A genetic test for MLD?

There is some evidence of steps towards modernization. The UK Government’s Department of Health & Social Care (DHSC) launched a Rare Disease Action Plan for England in February 2022. The first priority of the plan was to improve how decisions are made on newborn screening for rare diseases. Genomics England is running a pilot consultation to explore the possibility of genomically screening every newborn in the UK. This approach would enable more conditions to be captured but would still require specific conditions to be added to a screening panel. It’s unclear whether MLD will be among the conditions added to Genomics England’s initial panels and the results of a 2022 consultation on the topic have not been released.

Meade points out that newborn screening and post-symptomatic testing are two very different processes: “If you are looking at a healthy individual’s genome, there's a lot less you can conclude from it than if you're looking at [a patient] with a very clear illness affecting a particular body system in a certain way.”

There are also signs of change in how the UK weighs up treatments for rare disease. NICE conducted a major review of how it evaluated applications in January 2022. Meade says the community is waiting carefully to see how the revised approach serves people with rare conditions. Separately, a new roadmap toward approval, called the Highly Specialized Technology (HST) pathway, was commissioned by NICE in 2019. Designed for rare and very rare diseases, Meade says that NICE appears to only be using it for a limited group of incredibly rare conditions. While that has led to approval for drugs like Libmeldy, Meade hopes that this narrow approach will be widened in the near future.

This case-by-case process appears to be serving its purpose for now, but as researchers improve their understanding of the genetics underlying rare diseases and advance gene therapy treatments, that balance may shift. “One doesn't have to be an analyst of the whole system to think that potentially it isn't sustainable for all rare conditions,” says Meade. A treatment that costs millions but saves young lives and is only used sporadically may be judged as economically viable by NICE, but if we develop similar treatments for larger and larger patient populations, will that cost–balance assessment shift? Meade points to discussions in the European Union around risk sharing between nations as a potential model for other healthcare systems.

“I'm hopeful,” he concludes, “that we don't have to see patient groups with placards outside Parliament anytime soon because that means there are seriously ill people who are not accessing a medicine that they could do if decisions were different.”

“A second chance at life”

Connie and Joe’s stories show that every decision to fund or not fund a rare disease treatment carries a human cost that cannot be reduced to numbers on a spreadsheet. After treatment, Joe was required to return to Italy once or twice a year for follow-up tests. Clinicians, nurses and hospital staff have been a constant in his life for as long as he can remember. Joe’s last visit to Milan, finishing his treatment journey, was in December 2022.

Now 12, Joe gets ready for school, attends Scouts and other extracurricular activities – he loves watersports and canoeing – and complains about homework just like his peers. “While this may seem small and inconsequential to most,” says Nicola, “Anybody who has witnessed the effects of MLD will understand we take nothing for granted.” Connie, who loved reading and writing before her diagnosis, passed away last July. She was 13.

Nicola says that she’s aware of several children who have now been able to access Libmeldy free of charge on the NHS. That knowledge “brings many emotions” for her family – devastation that another child has had to reckon with MLD, and delight and relief that another child has been given what she calls “a second chance at life.”

The battle against rare diseases is ongoing. Developing a successful treatment and screening program is an endeavor that can take decades. But the rewards for children like Joe are boundless and the price of failure is too great.

In Italy, Fumagalli is working on a pilot program to enable metabolic heel prick testing of newborns with MLD. If the pilot is successful, she hopes the program will be rolled out nationwide. In the UK, a campaign to get a similar scheme up and running remains mired in bureaucracy. Nicola recalls an incident from shortly after her children were diagnosed. “I asked a metabolic pediatrician why MLD wasn’t screened for. He shrugged his shoulders and flippantly told me that the UK had one of the worst levels of [newborn screening] in the western world. This needs to change, it’s immoral and shameful; MLD can be screened for and it can be treated. It should not take the life of one sibling to save the life of another.”