- Doctors in the United Kingdom have used a revolutionary gene therapy to cure a toddler who has a rare genetic disorder—called MLD—that is usually fatal.
- At £2.87 million ($3.42 million), the treatment is the most expensive therapy ever approved for use in the U.K.’s National Health Service.
- The therapy, marketed as Limeldy, can only save children who have yet to develop symptoms of the disease.
- Therefore, doctors and families affected by this condition are calling for all children to be screened for MLD at birth.
Children who inherit a rare genetic illness called metachromatic leukodystrophy (MLD) experience a progressive loss of their ability to think, move, and sense the world around them.
They eventually become unable to walk, swallow, speak, hear, see or respond to stimuli.
Most children who develop the infantile form of MLD die by the age of five.
Around one in 100 people carry the faulty gene that causes MLD. However, the gene in question is “recessive,” which means that only children who inherit a faulty copy from both of their parents will develop the condition.
As a result, MLD is rare and affects only around one in 40,000 babies born in the U.K..
Estimates suggest that fewer than 50,000 people in the United States have the disease.
The gene for MLD makes a defective version of an enzyme. The job of the healthy enzyme, known as arylsulfatase A (ARSA), is to break down fatty substances called sulfatides in the white matter of the brain and spinal cord.
Sulfatides are a vital component of myelin, which is the fatty sheath that protects and insulates nerve cells.
In children with two copies of the defective gene, however, excessive amounts of sulfatides accumulate in the myelin sheath, which disrupts the nerves’ activity and causes inflammation.
Dr. Simon Jones, who treats children with MLD at Royal Manchester Children’s Hospital in Manchester, U.K., says that a mistake in a gene prevents the body from making an enzyme.
“The job of that enzyme is to break down a really important chemical for how your brain functions and works, and so it gradually builds up and builds up in the brain until a sort of catastrophic point, usually about the age of 2, when children start to lose all of those abilities,” he explains on BBC Sounds.
Doctors can use bone marrow transplants from healthy donors to treat patients, but this only delays the progress of the disease.
Another possible treatment would be to inject patients with the working enzyme that they are unable to make for themselves. However, the enzyme is a large protein molecule that can’t cross the blood-brain barrier.
Gene therapy for MLD
In the past few years, doctors have conducted successful clinical trials of a new form of gene therapy called atidarsagene autotemcel, marketed as Libmeldy, which provides a healthy gene to make the enzyme.
The therapy involves collecting stem cells from patients’ blood. The stem cells, which originate in the bone marrow, have the ability to develop into a variety of blood cells.
Doctors send these stem cells to a lab in Italy, which uses a modified virus to insert healthy copies of the gene for the enzyme into their DNA.
Meanwhile, the children undergo chemotherapy to destroy any remaining, unmodified stem cells in their bone marrow.
Finally, doctors inject the modified stem cells back into their bloodstream. The cells migrate to the bone marrow, where they start to produce blood cells that can make the working enzyme.
In January 2022, researchers in Italy, who conducted a clinical trial of Libmeldy, concluded that the treatment was effective in most children who received it in the early stages of the disease.
A few months later, in March 2022, the National Institute for Health and Care Excellence in the U.K. approved the drug for use in the NHS.
The BBC recently reported the story of one of the first children to receive the treatment — a 19-month-old toddler called Teddi Shaw — at Royal Manchester Children’s Hospital.
World’s costliest treatment
At the time of its approval, the treatment was the most expensive in the world, at a cost of £2.87 million ($3.42 million) per patient. Another gene therapy, approved recently in the United States, has now taken the title of the world’s most expensive treatment.
Libmeldy remains the most expensive treatment ever approved by NICE (though the BBC reports that the NHS has negotiated a confidential discount on the list price).
Its cost may seem excessive, but it took a British company, Orchard Therapeutics, 20 years to develop — from animal studies in the early 2000s to the first clinical trials in 2010.
The co-founder and CEO of Orchard Therapeutics, Professor Bobby Gaspar, M.D., told the BBC in a film about the new treatment that it’s been “a very long journey” to develop and bring such a therapy onto the market.
Prof. Gaspar is an expert in pediatrics and immunology at Great Ormond Street Hospital for Children in London, where he has led clinical trials of several gene therapies.
In addition, the price must be high because doctors estimate that only seven or eight children a year in the U.K. will be eligible for Limeldy.
Calls for universal testing
Tragically, many children are only diagnosed with MLD after an older sibling has become seriously ill. By the time the older child has started to develop symptoms, it is already too late to control the progress of this fatal disease.
The BBC report reveals how Teddi’s older sister, three-year-old Nala, is now unable to walk or eat, and is losing her sight.
Researchers, doctors, and the families of children with MLD have therefore called for the screening of all newborn babies.
Currently, a heel-prick blood test of all newborns in the U.K. is used to screen for nine genetic conditions, including sickle cell disease and cystic fibrosis, but not MLD.
Royal Manchester Children’s Hospital is conducting clinical trials of gene therapies for two other rare genetic disorders, Sanfilippo and Hunter syndromes.
“We are letting our children down by not screening for these devastating conditions because they are so preventable if you can identify them at birth,” says Prof. Gaspar.
How to test for MLD
Medical News Today asked Dr. Jones whether a suitable genetic test for MLD already exists.
He explained that doctors at the Royal Manchester Children’s Hospital currently use a biochemical test to screen for the condition rather than a genetic test.
They can measure either the level of sulfatides, or the enzyme—ARSA—in patients’ blood.
But testing for the enzyme gives a lot of “false positive” results, said Dr. Jones. In other words, it would give too many positive results for children who do not have the faulty gene.
“The sulfatides, however [a]re very robust and can be measured by standard newborn screening instruments,” he said.
“Genetic testing is most likely to be employed as a second-tier test [to confirm the diagnosis],” he added.
A recently published study, which Dr. Jones co-authored, concluded that screening all newborns for MLD would be cost-effective for the NHS.
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