Brenden was the first patient enrolled in what became a nine-patient, four-center trial that also involved patients at the National Institutes of Health (NIH) in Maryland, the University of California at Los Angeles, and Great Ormond Street Hospital for Children in London.
The trial, funded by the NIH and the California Institute for Regenerative Medicine, was staged, with treatment of subsequent patients dependent on the outcome for those before them. Brenden went first and, in December 2015, doctors took a sample of his blood stem cells and sent them to a cell manufacturing facility run by Professor of Medicine Jerome Ritz at the Dana-Farber Cancer Institute. There, an engineered virus inserted a corrected copy of the malfunctioning gene into the cells’ DNA.
Researchers then multiplied the engineered cells to create a population of Brenden’s own cells that could be transfused back into him. Brenden, meanwhile, had undergone chemotherapy to reduce the population of malfunctioning cells and create a niche in his bone marrow for the new ones.
After the transfusion of corrected cells, Brenden returned to Ohio, where he remained isolated at home for three months as the new cells multiplied and his immune system rebooted. The result of all this, Williams and other investigators hoped, would be that at least 10 percent of the resulting neutrophils would function normally, enough so that Brenden’s immune system would provide protection similar to that of a non-CDG sufferer.
The results exceeded expectations. Months after the transplant, tests found roughly half of Brenden’s neutrophils worked normally, clearing the path for the second subject to begin treatment.
Of the trial’s nine patients, two died of illnesses related to their CGD but unrelated to the trial, Williams said. Their deaths, he said, are an unfortunate function of the fact that the people recruited for clinical trials are often very sick, with few remaining options.
“Unfortunately, these kinds of early trials often take patients in dire straits, so sometimes you have bad outcomes related to pre-existing conditions,” Williams said.
Williams said the remaining enrollees have seen similar results to Brenden’s, with improved health and functioning neutrophil counts above the trial’s 10 percent target. In addition, none have shown signs of a negative side effect seen in earlier trials, a preleukemia condition called myelodysplastic syndrome.
“We’re able to reconstitute the activity that’s missing in these neutrophils,” Williams said, “and the activity levels are substantial enough that they appear to protect from infections of the type you get if you’re a CGD patient.”
Though the therapy has proven effective, questions remain as to its durability. Previous CGD gene therapy trials also saw improvement in the body’s ability to fight infection, but they faded over time. Though the effect in the trial’s oldest patient — Brenden — has shown no sign of fading, Williams said it’s nonetheless premature to call it permanent.
“When you talk about a cure, you’re talking about decades rather than years, so I think it’s too early to tell,” Williams said. “The longest patient is now [Brenden] … with stable engraftment of those genetically modified cells, so it’s going to be a while before anyone can talk about permanent cure. But the data so far are quite encouraging that the effectiveness is stable over time.”
That uncertainty is one reason trial subjects will be followed for 15 years. It’s also something Brenden said he has accepted, part of the one-day-at-a-time philosophy he honed during the ups and downs of life with CGD.
“I’m not fearful of it coming back,” he said. “I accept and understand that it can. I knew that when I signed up for this. Fear was definitely part of it [living with CGD], but then, after a while I kind of got used to the fear. I wasn’t really afraid of dying anymore because I’d been there. I’d been to the point of having 106-degree fever for two weeks, lying in a hospital bed, planning my funeral.”
If the gene therapy stops working, he added, “I’m not going anyplace new … It’s not like I’m going to get a new disease or illness. It goes back to the old normal.”
Steps on a path to the future
Despite that hard-nosed view, hope for a cure is nonetheless part of the trial. After all, the long-term promise of gene therapy lies in the prospect of treating genetic diseases at their roots, curing them once and for all. One of Brenden’s doctors, in fact, has already seen enough, writing in case notes, according to Becky, that he considers Brenden’s improvement “to truly be a miracle of modern medicine” and “that it would appear that he is cured.”
Permanent or not, the improvement has lasted long enough to cause very real changes to Brenden’s life — changes that don’t go unnoticed by former teachers, youth group leaders, and others who knew a kid who was constantly sick, getting sick, or recovering from being sick, Becky said. When they ask after him and she describes the young man taking college-level courses with an eye on medical school, she said their surprise is apparent.
“They can’t possibly imagine what I describe now, because it’s just not the person that they knew: low energy, not a lot of effort,” Becky said. “He and I talked and it’s about going through a time of illness and then another illness and another illness and getting to the point of thinking, ‘What’s the point?’”
Brenden has also noticed the change, Becky said, not just in himself, but also in how people react to him.
“Something came up — I don’t remember what — and we were discussing how to handle it. He said, ‘In the past, this is what would have happened.’ And I said, ‘Brenden, people are reacting to you as a healthy adult. The expectations have changed,’” Becky said. “‘People are responding to you as if you are going to have 60, 70 more years on the Earth and they’re expecting a different kind of participation, contribution, than when you were a sick kid.’”
Gene therapy’s expanding promise
The rigors of gene therapy wouldn’t be Brenden’s first choice for CGD patients whose conditions are controllable with antibiotics, but, if the therapy is ultimately approved for broad use, he believes it should be made available to those seriously ill with repeat infections.
Becky, drawing on her experience as an oncology nurse at Ohio State’s James Cancer Hospital, said she’d actually prefer gene therapy over bone marrow transplants. She’s seen too many transplant patients struggle with graft-versus-host disease, trading one problem for another. The advantage of gene therapy, she said, is that because it uses the body’s own cells, it eliminates entirely the risk of rejection.
Results of the CGD trial have been positive enough that Orchard Therapeutics, on whose scientific advisory board Williams sits, plans to conduct a registration trial for the treatment. If successful, the trial would lead to FDA approval for broader use.
If it gains FDA approval, the CDG treatment would be the latest in an expanding toolbox of gene-based treatments coming to market after decades of research and development. At the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center alone, therapies are being developed for hemophilia, severe combined immunodeficiency (aka bubble boy syndrome), thalassemia, the brain disease adrenoleukodystrophy, and spinal muscular atrophy.
In addition, a recently developed treatment for sickle cell disease, which affects millions around the world, is promising enough that in December it attracted a $ 1.5 million grant from the Bill and Melinda Gates Foundation. The grant will support further development of the therapy with an eye toward use in low-infrastructure, developing world settings.
“I think it’s very clear that this [gene therapy] is becoming a part of our therapeutic armamentarium, for still a limited number of diseases, but an ever-expanding number of diseases,” Williams said. “I’ve been doing this for 30 years and I’ve always been pretty sanguine about how things are moving into the clinic, but it’s a very, very hopeful time right now.”
This trial was funded by the NIH and the California Institute for Regenerative Medicine.