In the early months of 2014, Brandon Rojas was a typical 6-year-old: healthy with a sunny disposition, a love of sports, and a passion for the superhero Iron Man. But by the end of the year, he had a terminal diagnosis, fast-diminishing mobility, and was no longer able to read his favorite comics.
Brandon’s cerebral adrenoleukodystrophy (ALD), a neurological disease made famous by the 1992 movie Lorenzo’s Oil, was just the beginning. His parents soon learned that his younger brother, Brian, then just 4, had the same genetic glitch as the big brother he idolized.
The family had two options: They could either give Brian the standard medical approach to ALD—a bone-marrow transplant that carried a 20 percent chance of death—or they could sign him up for an experimental hematopoietic stem-cell gene therapy that had only been tried a handful of times. (Hematopoietic stem cells are cells that can give rise to different types of blood cells and some brain cells; gene therapy tinkers with the genes of those cells to correct the genetic flaw.)
After long discussions with doctors, Liliana and Paul Rojas opted for the gene therapy option, fixing the single genetic glitch that causes ALD.
Today, they’re thrilled today they did.
In a study published last Wednesday in the New England Journal of Medicine that followed 17 boys who received the gene therapy, 15 of them—including Brian—continue to show no major symptoms of the disease at least two years after receiving the gene therapy. ALD symptoms typically include learning and behavioral problems, muscle spasms, seizures, and loss of hearing and vision.
David Williams, Brian’s doctor at Boston Children’s Hospital and the paper’s senior author, has worked on the development of gene therapies since the early 1980s. He described the trial’s success as “a dream come true.”
“It’s a great technology and we’re very excited about it,” he said.
The genetic mistake in cerebral ALD causes long-chain fatty acids to build up in the brain, essentially clogging it with trash and damaging the myelin sheaths that wrap around nerves cells to insulate them, speeding brain signals. Gene therapy corrects the mistake, growing new, healthy glial cells that can clear out the trash.
The therapy is complicated. First, doctors gave the boys a drug that encouraged blood stem cells—precursors to blood and certain brain cells—to leave the bone marrow for the bloodstream, where they could be easily collected. In a lab, scientists used a virus to infect these blood stem cells and inserted corrected genes into them.
After the boys received chemotherapy to kill off their remaining blood stem cells, the corrected cells were infused into their bloodstream, eventually returning to the bone marrow. The corrected stem cells began producing healthy blood cells and glial cells, though the process can take as long as a year.
Because the boys, aged between 4 and 13, received their own doctored cells rather than someone else’s, they didn’t have to worry about their body rejecting the healthy cells, as is often the case with bone-marrow transplants.
Some faulty cells remain, Williams said, but he thinks that as long as 20-30 percent of the faulty cells are corrected, the disease will be stopped. The 15 boys who fared well in the trial were producing functional ALD protein, which their bodies had been unable to produce prior to gene therapy. None suffered any major functional disabilities, such as losing hearing or ending up in a wheelchair, which would be unlikely without treatment.
“If they hadn’t been provided this option they would not have done very well,” said Nick Leschly, chairman of bluebird bio, the Cambridge, Massachusetts-based biotech that developed the gene therapy and is testing similar gene therapies in beta thalassemia (another inherited blood disorder) and in the blood cancer multiple myeloma. “Fifteen of the 17 have what’s really a good clinical outcome.” One of the boys who did not do well died before the repaired cells could make their way into his brain. The other boy’s parents pulled him out of the study so he could get a stem-cell transplant, which they hoped would offer a more reliable long-term outcome. Unfortunately, he died shortly after the transplant, Leschly said.
Eight more boys are now being added to the clinical trial. When that trial is complete, bluebird is expected to use the results to ask the U.S. Food and Drug Administration to approve their Lenti-D viral gene therapy for use in boys with ALD.
Williams, also president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, said only time will tell if the gene therapy continues to protect the boys, as everyone hopes, and whether there will be any unexpected side effects. His next experimental use of gene therapy will be against sickle cell disease, which affects a much larger number of people around the world. The FDA recently approved his gene therapy trial in sickle cell, which made Williams “absolutely ecstatic,” adding that animal and lab data on the approach seem promising.
Brian Rojas is now 7 and in second grade—past the point where his brother’s decline began—and playing all the sports his brother used to love. Brandon, 10, is in a wheelchair, unable to eat or communicate, though he still smiles and laughs at his family’s antics. (The family maintains a Facebook page on Brandon’s status and their efforts to raise awareness about ALD.)
It’s “very frustrating” to watch his older son continue to decline, Paul Rojas admits. If the family had known earlier about Brandon’s genetic condition, he might still be wrestling on the living room floor with Brian or chasing him down on a sports field.
Rojas, of Dover Plains, New York, now lobbies for universal newborn screening for ALD—which has been approved at the federal level, but only by a handful of the 50 states, including New York. “This is a treatable disease if caught early,” he said.
The Rojas’ are still hoping for a miracle treatment that will help Brandon and other boys in more advanced stages of the disease. “My wife and I have made a pact to stay positive,” he said.