New Therapeutic Targets and Immunotherapy Approaches Emerge for Cerebral Small Vessel Disease
Key Insights
Researchers in Bordeaux have identified TRIM47 (search), a protective protein that helps maintain vascular integrity in the brain by activating the NRF2 (search) antioxidant pathway, opening new therapeutic avenues for CSVD.
Two strategies are being explored: antisense oligonucleotides targeting KEAP1 (search) to boost the TRIM47 (search)/NRF2 (search) pathway, and repurposing existing drugs like multiple sclerosis therapies that activate NRF2.
Helena Karlström's group at Karolinska Institutet received a Novo Nordisk Pioneer Innovator Grant to develop monoclonal antibodies that clear harmful NOTCH3 (search) protein aggregates in CADASIL (search), a rare genetic form of CSVD.
Cerebral small vessel disease (search) (CSVD), a chronic condition affecting the brain's smallest arteries, impacts more than 5 million people aged 65 and over in France alone and represents the second most common cause of dementia after Alzheimer's disease. Despite this substantial disease burden, no curative treatment currently exists—but two independent research efforts are now charting promising new therapeutic paths targeting the underlying biology of the condition.
CSVD progressively stiffens, thickens, or renders more permeable the tiny arteries that continuously supply deep brain regions essential for memory, attention, and coordination. Over time, the brain receives less oxygen and fewer nutrients, while the blood-brain barrier (BBB)—a highly selective filter between blood and brain tissue—becomes compromised, allowing unwanted substances to enter and contribute to gradual neurological deterioration.
TRIM47 (search): A Protective Protein and New Therapeutic Target
At the Laboratory of Cardiovascular Disease Biology in Bordeaux, directed by Thierry Couffinhal, and the Vascular Brain Health Institute founded by Stéphanie Debette, researchers have identified a protein called TRIM47 (search) (TRIpartite Motif containing 47) that plays a protective role in endothelial cells lining cerebral blood vessels.
"We have demonstrated that this protein plays a protective role in endothelial cells by helping to maintain vascular integrity and limiting the effects of oxidative stress," the Bordeaux team reports. The protective action of TRIM47 (search) appears to operate through the NRF2 (search) signaling pathway, one of the body's main antioxidant defense systems. When functioning properly, this pathway activates cellular repair and detoxification mechanisms. However, research suggests this protective response declines with age, making cells increasingly vulnerable to oxidative stress—a phenomenon the researchers liken to "biological rust" that gradually damages blood vessels.
Two Complementary Therapeutic Strategies
The Bordeaux group is pursuing two parallel approaches to translate this discovery toward clinical application. The first involves developing antisense oligonucleotides (ASOs)—chemically modified molecules designed to specifically recognize and reduce expression of KEAP1 (search) messenger RNA. KEAP1 normally inhibits the TRIM47 (search)/NRF2 (search) cellular protection system; by removing this inhibition, researchers hope to strengthen the natural defenses of cerebral blood vessels against aging and degeneration.
This work is being conducted in close collaboration with chemists from the European Institute of Chemistry and Biology and the Nucleic Acids: Natural and Artificial Regulations Laboratory in Bordeaux. "These close collaborations between biologists and chemists are essential for moving from the understanding of a fundamental biological mechanism to the development of innovative drug candidates that are more targeted, more effective, and potentially better tolerated," the researchers note.
The second strategy employs drug repurposing—testing medications already marketed for other indications, such as multiple sclerosis, that are known to cross the blood-brain barrier and activate the NRF2 (search) pathway. This approach offers a significant advantage: existing safety data could allow clinical trials to commence more rapidly than for entirely new drugs, potentially reducing both development timelines and costs.
Immunotherapy for CADASIL (search): Targeting NOTCH3 (search) Aggregates
In a separate but complementary effort, Helena Karlström, associate professor and research group leader at Karolinska Institutet's Department of Neurobiology, Care Sciences and Society, has received funding from the Novo Nordisk Foundation (search)'s Pioneer Innovator Grant Sustainability & Health programme to develop a new therapeutic approach for CADASIL (search), a rare but severe genetic form of CSVD.
CADASIL (search) is caused by mutations in the NOTCH3 (search) gene that lead to the accumulation of harmful protein aggregates in the brain's small blood vessels, gradually impairing their function. Karlström's group has previously demonstrated that immunotherapy can reduce these protein aggregates and improve blood vessel function in animal models. The new funding will support development of monoclonal antibodies that specifically target the harmful aggregates.
"It is both exciting and a great honour to receive this grant from the Novo Nordisk Foundation (search) and to have our work selected among so many excellent applications. Our goal is to contribute to the development of a new treatment that can improve the lives of the many people affected by cerebral small vessel disease (search)," said Karlström.
The project will evaluate treatment effectiveness, investigate potential adverse effects, and identify blood biomarkers that could eventually be used to monitor disease progression and assess treatment response in patients.
Detection and Current Management
Brain magnetic resonance imaging (MRI) remains the reference tool for detecting CSVD, capable of revealing characteristic lesions—microbleeds, lacunes, and white matter hyperintensities—sometimes present even before the first symptoms appear. However, no systematic screening is currently planned, primarily because MRI is an expensive examination difficult to extend to the entire population.
In the absence of curative treatment, prevention of cardiovascular risk factors remains the most effective strategy. High blood pressure, diabetes, cholesterol, smoking, and physical inactivity have all been shown to influence disease risk. "While waiting for targeted treatments to become available, certain measures have already demonstrated their effectiveness in preserving brain health: controlling blood pressure, engaging in regular physical activity, avoiding tobacco, adopting a balanced diet, and maintaining an active social and intellectual life," the Bordeaux researchers advise.
Both research programs remain at the preclinical stage, with several validation steps required before any application in humans can be considered. Yet the convergence of these independent efforts—one targeting oxidative stress pathways through TRIM47 (search)/NRF2 (search), the other clearing toxic protein aggregates through immunotherapy—signals a growing momentum toward treatments that address CSVD at its biological source rather than merely managing its symptoms.