Decades of dedication lead to drug trial for rare, fatal illness
Old cancer drug may treat devastating blood vessel disease
Huy MachJohn P. Atkinson, MD, (right) talks with patient Kim Morey, of Bentonville, Ark., a participant in the first clinical trial evaluating a potential drug therapy for a rare, fatal disease called retinal vasculopathy with cerebral leukodystrophy (RVCL). Atkinson, who directs the RVCL Research Center at Washington University School of Medicine in St. Louis, is leading the trial and has played a key role in research to describe the disease and develop a genetic test to identify it.
When Kim Morey was a young girl, a mysterious illness affected her family, striking relatives one by one at around the age of 40, she recalled.
“My dad’s grandmother had it, and then his mother and her sisters,” Morey said. “Then my dad’s cousin. And soon after that, my dad started showing symptoms.”
For years, the family didn’t understand what was happening. The relatives would wake up one day and discover blurry spots affecting their vision. Then there’d be weakness on one side of the body, sometimes accompanied by seizures or fainting spells.
Doctors were of little help. They misdiagnosed some of Morey’s family with brain cancer, others with multiple sclerosis or seizure disorders. And no matter what treatment the doctors tried, the symptoms continued to worsen. The disease acted like a series of small strokes that slowly stripped away the ability to see, speak, think clearly and control their bodies. Most died within 10 years of the first symptoms; none survived longer than 20 years.
In the mid ‘80s, not long after Morey’s father developed eye problems, he traveled from Arkansas to St. Louis on the advice of a cousin to see ophthalmologist Gilbert Grand, MD, then on the faculty at Washington University School of Medicine in St. Louis.
“Dr. Grand deserves a lot of credit for recognizing that the eye symptoms were something he’d never seen before and that many of the patients were related,” said John Atkinson, MD, the Samuel B. Grant Professor of Clinical Medicine at the School of Medicine. “He asked me to come by and see a couple of the patients, because he’d noticed there was something wrong in other organs as well, especially in the neurologic system.”
Atkinson is not a neurologist, but he’d solved a few puzzling medical cases, and his fascination with rare and mystifying ailments was well-known among his colleagues. Atkinson and Grand discovered that the patients’ tiniest blood vessels were wearing out prematurely, a scenario that damages tissues by cutting off oxygen and nutrients. The brain and eyes are least able to withstand a loss of blood flow, which is why vision and neurological problems were the first symptoms to appear.
In 1987, Grand and colleagues gave a name and a profile to the mysterious illness. They published the first report of a syndrome now known as retinal vasculopathy with cerebral leukodystrophy (RVCL). Their paper described the disease in seven patients. Six came from the same extended family — Morey’s.
In the 30 years since, Atkinson and colleagues have identified the faulty gene responsible for the disorder, discovered molecular processes that go awry inside cells due to the dysfunctional gene, and developed a genetic test for the disease. And they did all this on a shoestring budget, funded by small grants and fundraisers held by patients and their families. In 2016, a $4.1 million donation by Robert Clark and his partners at Clayco – a real estate, architecture and construction firm in St. Louis – allowed Atkinson and colleagues to establish an RVCL research center. The center has drawn researchers and physicians both in and outside Washington University. Clark’s wife Ellen died of the disease in 2010 at age 50.
And now, Atkinson’s team has launched the first clinical trial to evaluate a potential drug therapy for RVCL. Morey, who developed eye spots herself a decade ago, is one of the first four participants.
An Interim Report
In August 2017, Madonna Bogacki, Atkinson’s clinical research coordinator, busily welcomed families and researchers to a daylong RVCL symposium at the School of Medicine, greeting the family members with smiles and hugs. She’s known many of them for years. Several she counts as friends.
The families came to the Medical Campus to hear about progress in RVCL research since the last family conference, nine years before. Importantly, they came to find out whether, six months into the clinical trial, the researchers had managed to stop – or at least slow – the disease that had decimated their families.
Though RVCL is not a kind of cancer, the chemotherapy drug aclarubicin is the families’ current hope. Atkinson, Anna Richards, MD, PhD, and colleagues discovered in 2007 that RVCL was caused by mutations in the gene TREX1. Recently, Nan Yan, PhD, of the University of Texas Southwestern Medical Center, found that the mutant protein leads to a build-up in cells of a special type of sugar. Giving the cells aclarubicin brings the levels of the abnormal sugars down to near normal in mouse models of RVCL and in cells from human patients.
It is not at all clear why sugar inside cells might cause tiny blood vessels in the eyes and brain to fail. But the disease is untreatable and lethal, and aclarubicin appeared to help in experiments leading up to the trial. The FDA approved a clinical trial in late 2016, and the first participants started on aclarubicin that December.
The trial is tiny – the FDA approved a maximum of 20 participants, and only four have enrolled to date – mainly because there are so few people who could take part. Just 28 families worldwide are known to carry RVCL mutations. And of those, only people whose disease is advanced enough to be detectable on a brain scan are eligible to participate.
“This disease progresses slowly and first manifests in middle age. If you look at mutation carriers at, say, age 25, you usually don’t see significant changes in brain or eye exams,” said Kathy Liszewski, an assistant professor of medicine. “The therapeutic trial follows patients who already have brain and eye lesions so we can see whether taking the drug reduces or changes the number or character of the lesions.”
The neurological evaluations are being conducted by Andria Ford, MD, an associate professor of neurology.
Bogacki tried her best to find more people for the study. Two decades ago, when Atkinson and colleagues were searching for the disease’s genetic roots, they gathered blood samples from dozens of family members. There was no treatment at the time, so some donated their blood to help with the research but asked not to be told the results.
But the game changed once there was a drug candidate.
“We tried really hard to find family members,” Bogacki said. “I called every phone number I had collected over the past 20 years. We sent a two-page family update about the clinical trial to their last known addresses, asking the RVCL family members to call us. So far we have been able to enroll four members in the trial. They are certainly pioneers, and I’ve found them to be inspiring and courageous.”
At the family conference in August, Atkinson delivered an interim report on the clinical trial. The results were encouraging but not definitive. The lesions hadn’t gotten smaller – but it was possible that they had been prevented from getting bigger and that there were fewer new lesions. Atkinson declared himself undaunted. The trial, he announced, would continue with a higher dose of the drug.
Family members mulled over the results. Brother and sister Bryan and Allyson Schwartz, whose mother died of RVCL just before the trial started, were philosophical.
“I’m not enthusiastic about these results, of course, but we still have 20, 25 years,” Allyson said. Her mother and a maternal uncle started showing symptoms in their 50s and 60s. “That’s plenty of time for them to come up with a treatment.”
Meanwhile, conference participant Jessie Wheeler cried softly to herself while her mother hugged her. Wheeler’s father died a few years ago of the disease, and her grief had resurfaced at the conference. Another participant walking by paused to say kindly, “There are still good things in life.”
Moving Forward
Work continues toward a treatment for RVCL. Jonathan Miner, MD, PhD, an assistant professor of medicine, is planning another clinical trial with a different therapeutic. Miner, Liszewski and other basic scientists continue their experiments to better understand the disease and ultimately find the best therapeutic to treat or cure RVCL.
And for now, the aclarubicin clinical trial is slated to go on with dose increases every few months until there is clear evidence of improvement or the side effects become too toxic. By August of this year, the trial will have generated 18 months of data on three patients and 12 months on one patient.
“Dr. Atkinson likes to say that he’s not going to retire until he finds a cure for RVCL,” Bogacki said. “If he won’t, then I won’t either. We’re not going to give up on this. We’re getting closer all the time.”
