John Atkinson became a birder in fifth grader when his teacher told the students to put away their science books and follow her outside. Today, he still boasts being the first person in Kansas to spot a pine grosbeak, a type of plump, round-headed finch.

But it was at the National Institutes of Health’s Laboratory of Clinical Investigation in the early 1970s that his eye for the rare turned to diagnosing perplexing medical cases. When he went on to Washington University in St. Louis in 1974 and soon thereafter became head of the rheumatology division there, his colleagues knew to turn to him for hard to crack cases.

One such colleague was Gilbert Grand, an ophthalmologist at the Washington University School of Medicine, who called in Atkinson when he came across a family where the family members developed visual difficulties in their forties, but also had a cluster of other symptoms including premature death that lead him to believe there was more than a matter of an eye disease at work.

“Nobody knew what to do about this until we found the gene,” said Atkinson. “Once we had the gene, we could show this was an autosomal dominant disease and we had families around the world with it. We then began to think about how to do the next thing. One was the discovery of it. Two was the gene. Three was the treatment.”

Atkinson and Grand originally called the condition cerebroretinal vasculopathy. A researcher at the University of California, Los Angeles described a family that could trace a similar sounding condition back three generations. She named the disease hereditary endotheliopathy with retinopathy, nephropathy and stroke. In the 1990s Dutch researchers published a report of a family with a similar disease, but with a history of migraine headaches. They called the disease hereditary vascular retinopathy. They all suspected they might be identifying the same condition and collaborated in finding the answer.

It would take some 20 years since Atkinson and Gilbert began their work to find the genetic mutation underlying the condition. In 2007, they coauthored a paper with their other collaborators in Nature Genetics that reported that these patients had mutations in the tail end of the gene TREX1. They settled on the name for the condition as retinal vasculopathy with cerebral leukodystrophy or RVCL.

A little more than 10 years later, backed with $4.8 million from the Clayco Foundation, Atkinson is heading the RVCL Research Center at Washington University and in a few weeks will get the first look at data from a small early-stage clinical study to see if a cancer drug used in Asia might be able to stabilize the disease mechanism in RVCL and halt or slow the progression of the disease.

RVCL is a rare genetic disease that begins to manifest itself in middle age through deterioration of eyesight caused by the premature aging and failure of tiny blood vessels. People with the condition suffer mini-strokes in the white matter of the brain. Life expectancy is between five to 10 years from the onset of symptoms. The disease is often misdiagnosed as a brain tumor, multiple sclerosis, or characterized as an unknown illness.

TREX1, the gene that causes RVCL, codes for the TREX1 protein, which repairs DNA and controls a specific kind of sugar machinery within cells. A mutation in the tail end of TREX1 produces a shortened version of the protein that causes it to end up in the wrong place inside cells and leads to the development of RVCL. There is no available treatment for the condition.

Nan Yan, a researcher at the University of Texas Southwestern Medical Center, who studies the TREX1 gene and made the discovery that the mutant protein causes a specific sugar to build-up in cells, found that in mouse models, the cancer drug aclarubicin was able to reduce the sugar levels in the cells. He was also able to show in cell lines created by Atkinson’s lab that the drug could partially correct the defect. Aclarubicin is approved in Asia but was never patented in the United States.

The RVCL Research Center has been conducting a small clinical study to see if aclarubicin can slow or halt the disease. In a few weeks, Atkinson will be getting his first look at data from the study and the first indication as to whether it may be providing any benefit to patients.

If the drug shows benefit, Atkinson hopes a drug company will eventually step in to complete the clinical development and commercialize the therapy. In the meantime, the center continues to conduct a natural history study of the disease and build a patient registry.

“We’d like to slow it down or anything to do to manipulate the cells,” he said. Ultimately, though, Atkinson expects the answer will be to develop a gene therapy for RVCL

But this ultra-rare disease may be able to elucidate a much bigger medical problem, according to Atkinson, who notes that about 20 percent of dementia cases are not Alzheimer’s-type, but rather small vessel-type. In some parts of the world, that number is even higher.

“Here we have an example where your blood vessels appear to give up the ghost when you are 40 rather than 80,” he said. “We’re trying to figure this out.”

August 15, 2018