Penn Study of Rare Disease Sheds Light on More Common Ones

Rare Daily Staff

Retinal vasculopathy with cerebral leukoencephalopathy is a rare and deadly condition caused by mutations to the TREX1 gene, which is supposed to direct the maintenance of the entire body’s DNA. A new study that unlocks the mechanism of the disease has implications for more common ailments.

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) affects about 200 people worldwide and is often misdiagnosed as lupus, multiple sclerosis, or cancer. The disease causes the breakdown of small blood vessels in the body, which can affect many organs, including the brain, eyes, kidneys, liver, and bones. Patients with the condition typically do not begin to have symptoms—such as memory loss, partial loss of vision, and small strokes—until their 40s or 50s. Eventually, the breakdowns can cause organ damage and failure, including brain atrophy and blindness. There is no cure or treatment, and many patients die within five to ten years of symptoms beginning.

In a study published in Nature Communications, researchers led by teams at the Perelman School of Medicine at the University of Pennsylvania and the Brain Research Institute at Niigata University in Japan found that TREX1 speeds up the typical process of DNA damage—a process some theorize is tied to every animal’s aging process. It offers another example of how studying rare diseases can elucidate more common ones.

“It seems that accelerated DNA damage in RVCL causes the premature aging of certain cells, including the cells in the blood vessel wall,” said the study’s lead author Jonathan Miner, an associate professor of Rheumatology at the Perelman School of Medicine. “If this is the case, then targeting TREX1 could have very broad implications for the treatment of many human diseases linked to aging, including cardiovascular diseases, autoimmune disorders, and cancer.”

Miner and his colleagues explored their hypothesis that the TREX1 mutation in RVCL caused instability within cells and damage that appears similar to breakdowns seen in radiation injuries.

They found that the mutation was interfering with a DNA repair process, which occurs when there is a break in both strands of DNA. This interruption of the process allowed DNA to be deleted, and cells prematurely aged and stopped dividing, which leads to overall premature aging and organ damage.

In addition to uncovering RVCL’s primary mechanism of damage, the researchers also found that the TREX1 mutation also displayed a cell-level vulnerability that mirrors those seen in people with mutations to the BRCA1 and BRCA2 genes, which cause breast cancer.  In fact, the authors found similar elevated rates of risk of breast cancer in patients with TREX1 mutations as in patients with mutations in the BRCA1 and BRCA2 genes.

They also found that the TREX1 mutation’s effect on DNA damage also makes people with it more susceptible to damage from chemotherapy.

The study’s findings provide a clearer picture for the types of treatments and medicines that could be pursued for people with RVCL. They could involve lowering levels of TREX1 in the body, correcting the mutation, or just blocking the gene’s DNA-damaging effects.

“Until those therapies are developed, we are working to figure out whether certain mediations already FDA-approved for the treatment of other diseases might be repurposed for RVCL or potentially impact TREX1 levels in the body overall,” Miner said. “TREX1 levels increase with age in multiple tissues in all humans—even in healthy individuals without RVCL—and we need to understand the processes linked to this.”