TREX1 is a gene that plays a crucial role in maintaining the integrity of the body’s DNA. However, recent research has revealed that individuals born with a mutated form of TREX1 can suffer from a rare and deadly disease known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). The groundbreaking study, published in Nature Communications, was conducted by teams from the Perelman School of Medicine at the University of Pennsylvania and the Brain Research Institute at Niigata University in Japan.
While the link between TREX1 mutation and RVCL was already established, the precise mechanism through which the gene causes damage was unclear. By demonstrating that TREX1 accelerates the process of DNA damage – a phenomenon believed to be associated with the aging process in all organisms – the researchers not only uncovered the destructive power of TREX1 in RVCL patients but also provided insights that extend beyond this specific disease.
“It appears that the accelerated DNA damage in RVCL results in the premature aging of certain cells, including those in blood vessel walls,” explained Dr. Jonathan Miner, the lead author of the study and an associate professor of Rheumatology at the Perelman School of Medicine. “Targeting TREX1 could have far-reaching implications for treating numerous human diseases linked to aging, such as cardiovascular conditions, autoimmune disorders, and cancer.”
RVCL affects approximately 200 individuals worldwide and is often misdiagnosed as lupus, multiple sclerosis, or cancer. The disease leads to the deterioration of small blood vessels throughout the body, impacting various organs including the brain, eyes, kidneys, liver, and bones. Symptoms typically manifest in the forties or fifties, with patients experiencing memory loss, vision impairment, and small strokes. As the condition progresses, organ damage ensues, potentially resulting in brain atrophy and blindness. Unfortunately, there is currently no cure for RVCL, and many patients succumb to the disease within five to ten years of symptom onset.
“We are optimistic that our research will pave the way for advancements in the treatment of RVCL patients,” stated Dr. Taisuke Kato, the co-lead author of the study and an associate professor of Molecular Neuroscience at Niigata University. “Our discoveries equip us with a better understanding of the underlying biological processes that occur in their bodies.”
Through investigations using animal and human cell models of RVCL, Dr. Miner and his team explored the hypothesis that the TREX1 mutation, which shortens the gene, triggers cellular instability and damage akin to that seen in radiation injuries.
They found that the mutation disrupts a crucial DNA repair process that occurs when both strands of DNA are broken. This disruption leads to the deletion of DNA, premature cell aging, and cessation of cell division, culminating in premature aging and organ failure.
In addition to unraveling the primary mechanism underlying RVCL, the researchers discovered that individuals with the TREX1 mutation exhibit cellular vulnerabilities reminiscent of those observed in individuals with mutations in the BRCA1 and BRCA2 genes, which are associated with breast cancer. Furthermore, the study revealed that people with the TREX1 mutation are more susceptible to DNA damage induced by chemotherapy.
“We are concerned that certain treatments may inadvertently exacerbate disease progression in some patients,” expressed Dr. Miner. “Chemotherapy, which has been utilized to treat suspected ‘autoimmunity’ in RVCL patients due to overlapping symptoms with autoimmune disorders, could potentially worsen the condition.”
The findings of the study offer valuable insights into potential treatment strategies for RVCL patients, such as reducing TREX1 levels, correcting the mutation, or blocking the gene’s destructive effects on DNA.
“While we work towards developing these therapies, we are exploring whether existing FDA-approved medications for other conditions could be repurposed for RVCL or modulate TREX1 levels in the body,” Dr. Miner added. “Given that TREX1 levels increase with age in all individuals – even those without RVCL – understanding these processes is imperative.”
Moreover, the study’s implications extend beyond the RVCL patient population, shedding light on the DNA damage theory of aging and its potential applicability to a spectrum of human conditions.
“By elucidating the role of TREX1 in RVCL, we may uncover mechanisms that link this gene to various human disorders, including normal aging,” Dr. Miner explained.
This groundbreaking research was funded by grants from the National Institutes of Health, the Rheumatology Research Foundation, and several other institutions in the US and Japan.
