The researchers are continuing to study CLR01 in animal models of various diseases and are working to secure funding for more animal studies. The investigators are also making improvements that would allow CLR01 to be administered in a pill or capsule rather than requiring an injection.
Neurologic Diseases Share Common Blood–Brain Barrier Defects
Although stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and traumatic brain injury each affect the CNS differently, they share common defects in the blood–brain barrier that can be traced to a single set of genes, according to a new study. The findings could yield new approaches for treating brain diseases.
To protect the brain from harm, endothelial cells lining the blood vessels around the brain form a barrier that lets only specific molecules move from the blood to the brain. In people with certain diseases or brain injuries, the barrier doesn’t work properly and can allow dangerous molecules or pathogens into the brain.
“Our goal is to identify the mechanisms that lead to this disruption of the blood–brain barrier in stroke, multiple sclerosis, epilepsy, ALS, and traumatic brain injury,” said Richard Daneman, PhD, fellow at the University of California, San Diego, and leader of the research team. “For these diseases, the blood–brain barrier dysfunction is a significant contributor to symptoms and disease progression, so if we can stop the endothelial cells from going down this path, we could possibly limit the progression and the severity of these diseases.”
To identify molecular pathways and genes that are important for blood–brain barrier dysfunction, Dr. Daneman developed a way to isolate blood–brain barrier endothelial cells and compare gene expression in cells from healthy brain tissue to cells from the brains of mouse models of stroke, multiple sclerosis, epilepsy, traumatic brain injury, and ALS.
“Even though the diseases we looked at all have different triggers, we see very similar genes changing in all the different diseases within the brain endothelial cells,” said Dr. Daneman. “The fact that we found a common pathway means we could potentially find a single therapeutic target that could stop these different neurological diseases from occurring or progressing.”
To learn more about the exact function of genes that they identified as being involved in blood–brain barrier dysfunction, the researchers plan to create genetically modified mice with brain endothelial cells that either overexpress or lack a given gene. “If we can develop methods to stop these genes from being turned on, we may be able to limit the blood–brain barrier dysfunction,” Dr. Daneman said.
Genetic Variability in the Platelet Linked to Increased Risk for Clotting
Coronary heart disease and stroke, two of the leading causes of death in the United States, are associated with heightened platelet reactivity. An underlying reason for the variability in the risk of clotting may result from a genetic variation in a receptor on the surface of the platelet, according to researchers. In addition, people with this genetic variant may be less protected from clotting and thrombosis when taking current antiplatelet therapies such as aspirin and other blood-thinning medications.
Antiplatelet therapy has helped to reduce mortality associated with heart attacks and strokes significantly. Some individuals taking antiplatelet drugs are not fully protected from platelet clot formation, however. For example, black individuals are disproportionately affected by these diseases, compared with white individuals, even after adjusting for clinical and demographic factors.
Benjamin Tourdot, PhD, a postdoctoral fellow on a research team led by Michael Holinstat, PhD, Associate Professor of Pharmacology at the University of Michigan in Ann Arbor, recently discovered a genetic variant in a key platelet receptor, PAR4, that enhances platelet reactivity and is more frequently expressed in blacks than whites.
Although the genetic variation is more common in blacks than in whites, it is relatively common in both races. Approximately 76% of blacks and 36% of whites express at least one copy of the gene responsible for the hyper-responsiveness.
To determine whether individuals with the hyper-responsive form of PAR4 may be less protected following a myocardial infarction or stroke even after receiving recommended antiplatelet therapy, the investigators compared healthy individuals and cardiac patients with and without the mutation for their responsiveness to PAR4. Participants were taking standard-of-care antiplatelet therapy (ie, aspirin and Plavix). The preliminary data demonstrated that, independent of race, individuals with a copy of the hyperactive variant of PAR4 have an increase in PAR4-mediated platelet reactivity, compared with individuals without the variant, even in the presence of antiplatelet therapy.
This research could identify the PAR4 T120A variant as a potential risk factor for thrombosis and would require a new approach to treating patients with this genetic variant, including the development of PAR4 antagonists. A greater understanding of which patients benefit the most from current therapeutic strategies and which patients remain at elevated risk for a thrombotic event will aid in the development of new therapeutic targets for at-risk populations.