Brenden Whittaker didn’t agree to gene therapy lightly. But he had been so sick for so long that the risk of the first-time-ever procedure would be worth it if that meant finally getting well.
“I really didn’t have any other options, health-wise,” Brenden said. “I’d been sick for four or five years. They’d done countless tests, countless treatments, and nothing was working. This was really, honestly, one of my last shots at getting healthy.”
The antibiotics that had been the young Ohio man’s ally against infection were finally failing, and doctors had been increasingly resorting to surgery, cutting out an infected lobe of his liver, half a right lung. Though the surgeries worked, removing the infection along with tissue, by late 2015 Brenden, his doctor, and his mother, Becky Whittaker — an oncology nurse who had guarded his health since his infancy — knew there were only a few bullets remaining in that particular gun pointed at solutions. Infection would keep returning, and he’d eventually run out of body parts to sacrifice.
Becky said that 2015, before the gene therapy, “was absolutely a horrible year. And I really, honestly, didn’t see him living much past that, the way that things were going.”
Since birth, Brenden has struggled with chronic granulomatous disease, or CGD, a rare immune disorder that affects the function of infection-fighting white blood cells called neutrophils. The condition changes the killing chemistry that occurs inside the cells and renders ineffective the engulf-and-destroy strategy they employ against the body’s invaders.
In late 2015, Brenden became the first subject in a CGD gene therapy trial at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. The trial, which sought to correct a dysfunctional gene that causes the disease, was led by center president David A. Williams, the Leland Fikes Professor of Pediatrics at Harvard Medical School and Boston Children’s Hospital’s chief scientific officer and senior vice president.
By all accounts the therapy worked. The three years since he was infused with his own corrected blood stem cells have been Brenden’s healthiest since 2009, when a series of infections began that robbed him of his junior year in high school, prompted surgeries, and, ultimately, led him to enroll in the trial.
Though his health hasn’t been perfect, he has fought off the occasional cold or flu with little more trouble than other sufferers, to his own and his mother’s relief.
“Each day that he’s free of infection, he’s able to go to class, he’s able to work at his part-time job, he’s able to mess around playing with the dog or hanging out with friends,” Becky said, “is a day I truly don’t believe he would have had beyond 2015 had something not been done.”
While the treatment has had the hoped-for physical effect, it’s had a mental impact as well. After years of illness punctuated by long nights when he wasn’t sure he’d have a next morning, the therapy has opened Brenden’s future for him.
“I didn’t have any kind of plan for the future,” he said of his mindset before the gene therapy. “I didn’t think I was going to need one. I was more focused on the ‘right then’ — getting healthy right then. … I’d never thought that long-term before because I’d been sick for so long.”
In the three years since the treatment, Brenden has worked toward an associate’s degree in health sciences at a nearby community college. He hopes to graduate this spring, completing academic work that he began before the gene therapy but that was repeatedly delayed because he kept getting sick.
Now 25, Brenden plans to transfer to Ohio State in the fall for a bachelor’s degree program. After that, he said, medical school is a possibility.
“Just being the patient for so long,” he said, “I want to give back. There are so many people who’ve been there for me — doctors, nurses who’ve been there for me [and] helped me for so long.”
From “fatal” to “chronic” to “cured”?
CGD is relatively rare, affecting just 1,500 Americans. Once called “fatal granulomatous disease,” the development of modern antibiotics transformed what was a certain killer into a lifelong battle against infection. Today, physicians guide CGD patients toward prevention as a primary defense. Patients typically take preventive antibiotics and interferon injections to boost their immune systems and keep infections from taking hold in the first place.
The strategy works, though imperfectly enough that the lives of CGD patients — half of whom don’t live beyond age 40 — are often punctuated by repeat hospitalizations to combat bouts of serious infection and development of the “granulomas” for which the condition is named. Granulomas are clumps of infected tissue that result when the body tries to wall off infections it cannot defeat. In severe cases, the granulomas themselves can cause problems, obstructing digestive passages and other critical pathways in the body.
When antibiotics no longer do the job, some patients receive bone marrow transplants, which can generate functioning neutrophils from a donor’s blood stem cells. The transplants, however, carry the risk of graft-versus-host disease, in which the transplanted cells attack the host’s tissues. That makes it critical that donor and patient are closely matched. It also means that for some, like Brenden, a suitable donor won’t be found.
Boston Children’s Hospital has a long history with CGD. The first diagnostic test for the condition was developed there in the 1960s by Robert Baehner, a fellow in the hematology/oncology program who later became Williams’ medical school research mentor. In 1986, Stuart Orkin, today the David G. Nathan Distinguished Professor of Pediatrics at HMS, identified the gene whose mutation confers CGD. The mutation in an individual gene makes the condition a promising gene therapy candidate because, unlike diseases traced to multiple genes, it provides a clear target whose correction could, in theory, mean a cure.
