Stanford Medicine offers gene therapy for a devastating pediatric neurologic disease

Stanford Medicine Children’s Health has become one of only four locations nationally to offer gene therapy for a devastating neurologic disease called X-linked adrenoleukodystrophy.

The new therapy, approved by the U.S. Food and Drug Administration in late 2022, halts brain complications of the genetic disease more commonly known as ALD. Without treatment, the complications can lead to severe, progressive neurologic problems such as seizures, blindness and deafness, and eventually a vegetative state and death.

Stanford Medicine experts helped conduct the clinical trial that enabled FDA approval for the new therapy, which is called elivaldogene autotemcel (marketed as Skysona and made by Bluebird Bio). The scientists have seen how much it improves on the traditional method of treating patients via stem cell transplant.

“What’s exciting about this new treatment is that patients do not go through the toxicity of a typical transplant,” said Ami Shah, MD, clinical professor of pediatrics, who led the Stanford Medicine arm of the clinical trial.

A typical stem cell transplant uses donated bone marrow from another person to provide patients with healthy cells that can halt the disease. But the process is arduous, requiring chemotherapy and carrying the risk that, in the recovery period, the donated bone marrow will attack the patient’s own tissue as foreign, a life-threatening complication called graft-versus-host disease.

In the new gene therapy treatment, instead of transplanting stem cells from another person, the patient’s own stem cells are removed, modified to insert the missing gene, then returned to them. Using the patient’s own cells eliminates many risks related to the transplant process.

“With this option, there is less chemotherapy and zero risk of graft-versus-host disease,” Shah said. “The immune system recovers quickly, and patients move on to normal life sooner.”

Shah’s team gave gene therapy to three patients during the clinical trials, which included a total of 57 patients across the country, and are now ready to offer the treatment to any patient who needs it. Stanford Medicine is currently the only site west of the Mississippi equipped to administer the new therapy.

Stanford Medicine’s pediatric hematologists are also starting to offer recently approved gene therapy treatments for the blood diseases beta thalassemia and sickle cell anemia. Stanford Medicine is one of about a dozen sites nationwide to offer the treatments. Tami John, MD, clinical associate professor of pediatrics, will lead patients’ treatments with these products.

A family’s trials

The Escobedo family of Colton, California, has seen the difference between the two treatments firsthand. Both of their boys, 14-year-old Israel and 8-year-old Ivan, were treated for ALD after showing the first signs of cerebral disease. Israel received a traditional stem cell transplant at a hospital in Southern California in 2016, before gene therapy was available. Ivan participated in the gene therapy clinical trial at Stanford Medicine, receiving his own genetically modified cells in 2021.

When Israel was diagnosed with cerebral ALD at age 5, his mom, Daisy Escobedo, was devastated. She had watched her brother die from the disease a generation earlier, at a time when medical science could not help.

She was relieved to learn that a stem cell transplant could stop progression of Israel’s disease, and said that her young son was brave about the treatment he faced.

“Israel was very mature at 5, very smart,” Daisy Escobedo said. “He even told me, ‘Give me what I need to get better’ right off the bat.” She and her husband, Jose, began preparing for several months of hospitalizations.

The disease, which affects about 1 in every 17,000 people, originates with an abnormal copy of the ABCD1 gene, located on the X chromosome. Because boys inherit only one X chromosome, from their mothers, they are much more likely to be affected by the disease than girls, who inherit an X chromosome from each parent. Girls who have one copy of the faulty gene are protected by the normal gene on their other X chromosome, while boys have no “backup” copy.

As a result, the severest form of disease, called cerebral ALD, occurs only in males.

The disease was depicted in a 1992 film, Lorenzo’s Oil, about a couple’s search for a treatment for their young son who was afflicted with ALD.

The faulty ABCD1 gene prevents patients from metabolizing fatty substances known as very-long-chain fatty acids, causing these molecules to accumulate in tissues around the body. In cerebral ALD, the buildup damages the brain, causing nerve fibers to lose their fatty, protective coating, known as myelin. Patients with cerebral ALD experience increasingly severe neurologic symptoms, and without treatment, they die about seven or eight years after symptoms first develop.

But, mysteriously, only about 35% to 40% of boys with the faulty gene develop cerebral ALD. Doctors cannot predict which children with the gene will develop the disease, but it typically appears between ages 2 and 12. Several states, including California, now screen all newborns at birth for the faulty gene. These tests enable doctors to begin monitoring children who carry it for early signs of neurologic complications.

Catching these signs quickly gives patients the best chance for successful treatment with a stem cell transplant or gene therapy, as these approaches can stop the brain complications from worsening but don’t reverse brain damage that has already occurred.

Surviving a stem cell transplant

Israel Escobedo’s stem cell transplant, completed when he was 6 with stem cells from an anonymous donor, was challenging. The chemotherapy that prepared him for the transplant was so debilitating that Israel needed physical therapy to regain strength afterward.

Once Israel received the donated cells, it took a long time for them to engraft — to begin growing and functioning inside his body. Donated cells provide the patient with the donor’s immune system, but recipients face impaired immunity until the cells become fully functional in their new home. Recipients can also suffer graft-versus-host disease.

I’m just grateful that they’re here with us now, able to do whatever they want.

Israel experienced both complications. “It was very difficult,” Daisy Escobedo said. Israel’s blood cell counts were low, and his immune system took a long time to improve after transplant.

“He kept getting infections, he had GVHD and skin complications, and had to go in and out of the hospital,” she said.

Five years later, when Ivan needed treatment, his physician recommended the gene therapy clinical trial. The family was thrilled when they learned that the process carried a much lower risk of complications.

“It was so smooth compared with Israel’s transplant,” Daisy Escobedo said. The chemotherapy to prepare for the procedure was so much gentler that, instead of helping Ivan with physical therapy exercises, she had to figure out how to handle his extra energy during his stay at Lucile Packard Children’s Hospital Stanford.

“When Israel was OK watching a movie or playing a game on his tablet, Ivan would be jumping off the bed,” she said with a chuckle.

When Shah’s team announced that Ivan had had enough preparatory chemotherapy, and that the genetic modification of his stem cells had succeeded and the cells were ready for him, “I was shocked: ‘Wait, that’s it?’” Daisy Escobedo said. “They said, ‘The transplant will be this day’ and I just couldn’t believe it.”

Ivan’s total hospital stay was shorter than his older brother’s and was not followed by infections or GVHD. While Israel still has some long-term effects of his bout with GVHD, today, “You would think Ivan never went through treatment at all,” Daisy Escobedo said.

Possible complications

Medical care for ALD has been gradually improving since the first stem cell transplant for the condition was performed in the early 1980s, but commercially available gene therapy treatment still has uncertainties, Shah noted. ALD gene therapy carries a risk of secondary leukemia, which means children must be closely monitored for early leukemia signs after receiving the treatment. However, given the severe and potentially fatal course of untreated cerebral ALD, experts who reviewed the treatment for FDA approval decided the risk was manageable, she added.

Patients who have a sibling able to donate bone marrow — meaning the brother or sister does not have the disease gene and is a close genetic match to the patient — will still receive traditional stem cell transplant, as the risk of complications is lower with sibling donors, Shah said. But many families, such as the Escobedos, don’t have this option.

Gene therapy treatment is expensive, at around $3 million, but U.S. health insurers have agreed to cover it, said Shah, adding that the treatment is not available in Europe because of the cost.

Normal kids

Today, Ivan and Israel (and their little sister, 2-year-old Isabella) are enjoying many normal kid pastimes. Israel recently finished eighth grade, and Ivan completed second grade.

“In school, Ivan loves math, and Israel likes a bit of everything, but especially social studies and history,” their mom said. “They love to swim and go off-roading with their daddy. We go on family road trips.”

Both boys now love playing baseball, and Ivan’s team recently won their Little League championship.

“I’m just grateful that they’re here with us now, able to do whatever they want,” Daisy Escobedo said.

The first day Ivan returned to school after his gene therapy in the fall of 2022, she relished the feeling of normalcy. “I was very emotional. I thought, ‘I feel like a normal mom.’ Instead of having him at home or the hospital, I can drop him off and he can enjoy being with his friends.

“It’s an amazing feeling.”