Gene Therapy Trial Wrenches Families as One Child’s Death Saves Another

The study, at the San Raffaele Telethon Institute for Gene Therapy, is proving dramatically effective in stopping metachromatic leukodystrophy, or MLD, an inherited disorder that strikes in childhood and destroys the brain’s white matter, leading to paralysis and dementia.

The therapy involves adding a correct copy of a single gene to a child’s bone marrow. But it only works well if it’s given before symptoms develop: by the time most children, including Liviana, are diagnosed it’s too late. The exception is when a family is alerted by one sick child that others are at risk. Then genetic and biochemical tests can discover if there’s a disease threat in younger children.

“It is gut wrenching; you lose one child and save another,” says Dean Suhr, president of the MLD Foundation, a charity based in Oregon. “That is a decision that no parent should make, but that is what has happened many times in this trial.”

The treatment appears to be the first gene therapy designed to act preventively, almost similar to a vaccine. Given early to infants, before scary symptoms set in at around two years of age, it appears to freeze or entirely prevent the rapid onset of the disease.

Italian doctors presented results on nine children in June in the Lancet. Eight of them had their disease progression interrupted or have reached school age with no illness at all. Alessandra Biffi, who initiated the trial in 2010 and is now a gene-therapy specialist with Harvard Medical School, says it’s still too soon to declare a permanent cure because the children haven’t been tracked for long enough.

“At a minimum, there is a substantial delay of the onset of the disease,” says Biffi. 

Gene therapy is making a historic jump from science project to real medicine. After three decades of false starts, the first curative gene treatment, for an immune deficiency disorder, was approved in Europe this year. Just like the MLD treatment, it was developed at the gene-therapy center in Milan, a hotbed of DNA science supported by national TV telethons that raise money featuring cases like that of the Prices’, a family with eight children, three of which were diagnosed with MLD, and which scrapes by on a house re-modeler’s income.

Both treatments have been purchased by British drug giant GlaxoSmithKline, which is pursuing commercialization of the therapies. By adding correct DNA code to cells, gene therapy has the potential to erase devastating illnesses with a one-time treatment. Andrew Shenker, the GSK vice president directing the MLD program, says gene and cell treatments could become as important as all of today’s pills and infusions.

The data from the siblings is especially powerful because each pair has the exact same DNA errors in their cells, and roughly similar genetic makeups. One therefore acts as an “untreated” control showing exactly what happens without gene therapy, and how well the other does by comparison.

Based on such potent data, GSK says it will be able to seek approval for the MLD treatment in 2017, even though so few children have ever received it. The paper’s concluding line recognizes the older siblings who acted as sentinels: “In memory of Baily, Valentina, Carlos, Dennis, Liviana, Mustafa, Randa, and Amany,” it reads.

Price still remembers the exact moment in 2010 when she noticed that Liviana’s right leg hung at a strange angle. Then the three-year-old began getting chills. It was the beginning of a parent’s nightmare as the toddler started hitting childhood milestones, except in reverse. Price noted everything on her blog: the day Liviana stopped walking. The last time she said mommy. Her last big smile.

They didn’t know it at first, but both Price and her husband, Brad, had one defective copy of a gene called ARSA. And because Liviana inherited both errors, and had no working copies, her body didn’t make an enzyme needed to clear certain molecules, called sulfatides, from her nerve cells. That destroyed their ability to maintain connections to other nerves.

The disease is very rare, affecting maybe one in 50,000 children born in a year. But the Price’s kids would all have a 25 percent chance. Doctors quickly tested the others—just three at the time—and Price almost blacked out when she learned her newborn Giovanni harbored the same genetic death sentence. Yet within days she had located the Italian trial and got Giovanni enrolled.

“Without her we wouldn’t have known,” Price says. “Liviana was given to us to save Giovanni.”

Children undergoing the treatment are dosed with busulfan, a chemo drug that destroys most of their bone marrow. But some marrow is removed and set aside first so doctors can use a virus to insert a working copy of the ARSA gene. After that, the corrected bone marrow is returned, and some cells make it to the brain where they turn into specialized glia, cells that manufacture the ARSA enzyme.

Parents are desperate to get in the study, including with children already showing symptoms. “They are asking to be treated. Absolutely, yes,” says Biffi. However, she says they are being refused for scientific reasons as the treatment takes at least months to have an effect, and isn’t expected to help much if a person’s brain is already in fast decline.

Instead, Italian doctors believe the earlier in life the gene is replaced, the better the results will be. In the future, says Allessandro Aiuti, the chief Italian doctor, MLD could be added to a list of rare diseases tested for at birth so children could immediately be spotted and have the chance for gene therapy. Other diseases might be treated the same way, making gene therapy like a childhood vaccine.

A pilot study got underway in Washington state this May of whether it’s feasible to detect MLD as part of newborn screening, which in the U.S. involves taking a spot of blood with a heel-stick and checking if the infant has any of about 30 to 50 metabolic disorders. Such inexpensive public health tests aren’t DNA tests; an MLD blood test would instead look for high sulfatide levels, but so far it’s not clear how accurate such a test would be. That is what the pilot study will find out.

The Italians covered the cost of Giovanni’s treatment and the Prices’ expenses, too, with money raised by the Telethon Foundation. But it has been difficult for Price to travel to Italy twice a year for medical follow-ups. When she once refused to return to Milan for a checkup, two Italian doctors instead flew to Omaha to test Giovanni’s bone marrow.

Price also disagreed with the Italians’ advice to get a prenatal genetic test during her two subsequent pregnancies to learn in advance if the fetuses would be affected, as she wouldn’t consider abortion. She had four more children, three of them in 2014 when she delivered natural fraternal triplets (there are one-in-8,100 odds of that). One of them, Cecilia, also had inherited the MLD genes. The Italians accepted the second baby into the study and treated her, too, at nine months of age. She is now two.

Giovanni has grown into a normal six-year old. He has already outlived Liviana, who was five and a half when she died. He remembers her as his “best friend.” When she was sick, he’d put toys in her hands even though she couldn’t play with them anymore. His mother says she has not explained to Giovanni that the reason he goes to Italy is because he has the same disease.

“I don’t want him to think that he is going to die, too,” Price says. “Someday, I will give him the conversation that he had the treatment and she didn’t, and that will make him sad. But those are big conversations to have with a six-year-old. Right now, no one would know standing next to him on the street that he really shouldn’t be here.”

Is the treatment a fix for good? No one can say. Cecilia is doing well, and so is Giovanni, who has aced his blood exams and kiddie IQ tests. He loves fancy clothes and cowboy boots. But Price says she is terrified that every growing pain or stumble is a sign the disease is starting. “I don’t want to say if I think it’s forever or not,” says Price. “I don’t want to jinx it.”