On a sweltering day in August 2021, as the engines of a hulking C-17 cargo plane drowned out pops of gunfire and Taliban rocket explosions around them, the young Afghan couple looked down at their 4-month-old son, Mohammad, and felt a shuddering wave of relief. But as the plane lifted above the dusty peaks that hug Kabul like a fortress of sandstone and schist, that feeling grew heavy with grief — for the parents and siblings they were leaving behind, and for Afghanistan, the only home they’d ever known. They did not know when, if ever, they would set foot there again.
Three years later, the Pashais are fearing for their family’s lives once again. This time the existential threat they face isn’t war, but a pair of faulty genes, silently passed down through their families for generations before detonating on American soil.
In October, Mohammad was diagnosed with a rare inherited disorder — metachromatic leukodystrophy. Genetic tests revealed his youngest brother, Sufyan, though he’s showing no symptoms, also has the disease. There’s a potential cure for Sufyan, a company offering it free of charge, and a team of doctors in Minnesota ready to administer it. But the Medicaid program in the Pashais’ new home state of Texas has said it won’t cover the hospital stay and other associated costs.
Hadisa, the boys’ mother, spends most days crying, when she’s not caring for Mohammad, who is no longer able to speak or hear and is often in and out of the emergency room. “We are in great distress that we are going to lose another child,” their father, who asked to be identified only by his first initial, due to the sensitive work he did for the U.S. military, told STAT through an interpreter.
For the last few years of the United States’ long, calamitous war, N. worked security for an elite unit of American-trained Afghan special forces, including at the Kabul airport after the city fell to the Taliban. He and his young family were among the lucky ones airlifted out of the country as part of Operation Allies Welcome. During the chaotic evacuation, tens of thousands of Afghans who assisted the U.S. were left behind.
After stays in refugee camps in Germany, then Florida, then Texas, the Pashais moved into an apartment in the Dallas area on New Year’s Day 2022. In the apartment complex, they met other newly arrived Afghans, made friends with their neighbors, and began to learn where to find halal markets and shops selling light linen kameez, a traditional tunic worn by Afghan men. N. received a work permit and got a job at a Mexican restaurant nearby. In July, his wife gave birth to their second son, Abubakar. A year later, their third, Sufyan was born.
Slowly, the growing family began to feel settled. Mohammad, the eldest, had not yet learned to walk, but doctors at the small clinic where they took the children said not to worry; that was normal. They began to think about where the boy would go to school.
Then one day last fall, Mohammad could no longer lift the front part of his foot off the ground. Back at the clinic, his doctor didn’t see anything wrong. N. brought him back repeatedly, until finally a blood test came back abnormal. A neurologist at Dallas Children’s Hospital ordered a MRI scan, which showed that big chunks of the white matter in his brain had disappeared, and a test of his cerebrospinal fluid found elevated levels of toxic chemicals called sulfatides.
Mohammad had a progressive disease called metachromatic leukodystrophy that was eating away at the nerves in his legs and the neurons inside his brain. There was nothing they could do but give him drugs to ease his pain.
Devastated and still in shock, N. listened as the doctors explained that the disease was something Mohammad had inherited. They advised testing the other sons as soon as possible for the presence of the same devastating mutation. Abubakar’s DNA test came back negative; he was only a carrier. But 4-month old Sufyan had two copies of the faulty gene, sentencing him to the same fate as Mohammad.
“It was a huge stress for us,” N. said. “But then the doctors told us that for this kid, therapy is possible. His disease is going to be curable.”
Although it’s not yet approved in the U.S., there is a gene therapy for metachromatic leukodystrophy, called Libmeldy. Produced by Orchard Therapeutics, it has been on the market in the EU since 2020, and is also authorized in the U.K., Iceland, Norway, and Switzerland. In the U.S., Libmeldy is available only through a compassionate use program and there’s only one center certified to provide the treatment, at the University of Minnesota Masonic Children’s Hospital in Minneapolis. Doctors there believe Sufyan is a good candidate for Libmeldy and are preparing to ask Orchard Therapeutics and the FDA to move ahead with treating him.
But when doctors asked the family’s insurer, Texas Medicaid, to cover the cost of an initial hospital visit to start the process of receiving Libmeldy, they were denied. The reason? Libmeldy is not yet approved in the U.S. (though it is expected to be later this year). Paul Orchard, a pediatric hematologist at the University of Minnesota, told STAT that in conversations with a representative from Texas Medicaid, he was told the program does not pay for experimental therapies. As of Monday night, a spokesperson for Texas Medicaid had not responded to STAT questions about its policies.
The Pashais are appealing the decision, arguing that they can’t wait for the expected FDA approval later this year because their son’s condition deteriorates every day. They are also citing a bill Texas legislators passed last year, guaranteeing coverage of routine costs associated with participating in clinical trials for the state’s Medicaid beneficiaries, contending that the same guarantees should be extended to patients receiving experimental therapies through a compassionate use program.
Texas Medicaid is expected to issue a ruling on the appeal this week. If nothing changes, two of the Pashai’s three children will perish before the end of the decade. Every day not knowing which way the decision will go is torture for the family.
Metachromatic leukodystrophy, or MLD, results from mutations that disable production of an enzyme called arylsulfatase A — one of the dozens of different enzymes that hang out in a cell’s lysosome, breaking down proteins, damaged cell parts, and other molecular debris. Without it, sulfatides build up in the brain and peripheral nervous system, stripping neurons of their myelin, the protective coating that allows them to quickly send electrical impulses to one another.
“Part of the problem with this disease is that most of the kids aren’t picked up until they’ve had substantial clinical manifestations,” said Orchard, who is also medical director of the Inherited Metabolic and Storage Disease Program at the University of Minnesota. About 100 kids with MLD are born in the U.S. each year, but it’s not one of the 60 or so inherited diseases for which hospitals routinely screen newborns. A diagnosis usually only comes after parents start noticing their child is sitting up or walking later than expected or having other motor problems, and tests for enzyme activity, sulfatide buildup, or gene panels confirm it’s MLD. But by then it’s too late.
“None of the interventions we’ve got restores lost myelin,” Orchard said. “So by the time you make a diagnosis, generally speaking, the kids are past benefiting.” Because of this, most of the kids with MLD that have received gene therapy have been younger siblings to an older affected brother or sister.
“I’ve had to tell way too many families there’s nothing we can offer them and their kids are going to die,” he said.
Unlike other lysosomal storage disorders where patients can be treated with infusions of the missing enzyme, MLD primarily impacts neurons that are tucked away behind the blood-brain barrier. Bulky enzymes can’t reach them. But immune cells have ways to slip past this barricade. Starting in the 1970s in the U.K., and later in the U.S., doctors began exploiting this vulnerability to treat MLD with bone marrow transplants. The donor stem cells give rise to blood and immune cells capable of making arylsulfatase A. If enough of them make their way into the brain, they can halt progression of the disease.
But it’s not very efficient, and bone marrow transplants come with chemotherapy, years of immunosuppressive drugs, and risks of rejection, graft versus host disease, and other complications.
Starting in the ’90s, researchers in Milan, Italy began working on a gene therapy that could do better. The idea was to add a healthy copy of the arylsulfatase A gene to blood stem cells collected from patients and then infuse them back. In 2010, the pharmaceutical giant GlaxoSmithKline acquired the rights to the Italian team’s gene therapy technology for rare diseases, which it later sold to Orchard.
In recent years, Orchard has made waves with its strategy of running small trials without a placebo group, which has led to multiple approvals and made it one of the most successful companies at getting gene therapy covered in European countries. In October, Orchard was acquired by the Japanese firm Kyowa Kirin for $400 million.
Orchard, the University of Minnesota physician, has no ties to Orchard, the company, which is based in Boston and London, other than sharing a fruit-tree-covered-hillside-evoking name. But a few years ago, the two Orchards began discussions about a clinical trial in the U.S. and setting up a site at the University of Minnesota. The company ultimately decided to forego that and instead approach U.S. regulators with data from its European trials.
The FDA is expected to make a decision on Libmeldy by March 18 of this year. In the meantime though, the agency and Orchard have been working with the team in Minneapolis to administer the gene therapy to kids there on a compassionate use basis. So far, four children have received Libmeldy at the University of Minnesota — the only place in the U.S. currently offering the treatment.
The Pashais and their doctors are hoping Sufyan will be the fifth. “This treatment doesn’t make anyone better; the goal of the gene therapy is to help prevent any additional damage from occurring, so the key is to identify these kids when they’re presymptomatic and intervene at that point,” said Orchard.
If the appeal fails, the Pashais will not get another chance. Their only remaining option would be a legal challenge, something for which they do not possess the funds to pursue.
It’s not the first time MLD patients have had to battle for coverage to get Libmeldy in the U.S. The first child treated at the University of Minnesota, a 4-year-old named Celia Grace, almost wasn’t able to go through with the procedure when the family’s insurer, BlueCross BlueShield of Alabama, threatened to back out.
“If it takes months to figure out the insurance side, that’s a problem because these kids may not have a whole lot of time,” Orchard said. Once a patient’s cells have been collected, it takes five to six weeks for the genetic engineering to be performed on them, followed by chemotherapy to make room for the cells. “It’s a rapidly progressing disease,” he said. “Anything else that delays it will put these kids at higher risk.”