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A gene target for stroke recovery?
LOS ANGELES—When one thinks of stroke, one thinks of a great many things, but almost always those thoughts orbit around restricted blood flow or blood vessels that are leaking or bursting. It’s not something we really think of in terms of genetics, except perhaps with regard to genes that increase the risks of developing conditions that lead to stroke.
But researchers at the University of California, Los Angeles (UCLA)—led by Dr. S. Thomas Carmichael, chair of the neurology department at the David Geffen School of Medicine at UCLA—made an interesting discovery that is based in genetics and might lead to better ways of reducing the aftermath of stroke.
Specifically, the UCLA team found that patients born without a gene called CCR5 recover better from mild stroke than patients with the gene. And, because the absence of the CCR5 gene is common in Ashkenazi Jews, the team partnered with Israeli researchers at Tel Aviv University to study the missing gene’s effect on brain function. Their findings were published recently in the journal Cell under the title “CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.”
Highlights of the paper were:
So, what is at the root of this genetic pathway, and what does an HIV pill have to do with any of this?
CCR5 plays multiple roles in the body, and one of them is that in HIV infection, the gene unlocks the cellular doorway that the virus must enter to infect the immune system. But CCR5 also plays a role in the formation of new neuronal connections, in that neurons produce CCR5 only during or after stroke. Deletion of CCR5 appears to promote recovery by enhancing plasticity, the ability of the brain to rewire itself after injury.
Put more technically by the authors of the paper, “We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.”
The current study in Cell has roots in—and builds upon—work done earlier at UCLA on mice and led by UCLA neurobiologist Alcino Silva indicated that suppressing CCR5 enhanced neurons’ ability to form new connections and rewire the brain after injury. Silva and his team also demonstrated in that 2016 study that maraviroc, an FDA-approved drug that targets CCR5 to slow HIV progression in patients, improved learning and memory in mice.
Because maraviroc blocks CCR5, Carmichael and his team hypothesized that the drug may also accelerate recovery from stroke. His lab partnered with pharmacologist Esther Shohami at Hebrew University to test the drug’s effectiveness in suppressing CCR5 in a mouse model.
“We found that maraviroc blocked CCR5 in mice and boosted the animals’ recovery from traumatic brain injury and stroke,” said Dr. S. Thomas Carmichael, chair of the neurology department at the David Geffen School of Medicine at UCLA. “The big question left to answer was whether eliminating CCR5 would produce the same results in people.”
In teaming with researchers in Tel Aviv—led by neuroscientist Einor Ben Assayag—who were already following 446 stroke patients in an observational study, Carmichael, Assayag and colleagues focused only on patients who had suffered mild or moderate strokes, documenting the patients’ improvements in walking, arm and leg control, and other types of movement.
“Einor’s lab had the patients’ blood samples and was evaluating their recovery from stroke after intervals of six months, one year and two years,” explained Carmichael, who is also co-director of the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “People missing the CCR5 gene showed significantly greater recovery in motor skills, language and sensory function.”
In addition, a year after stroke, patients missing CCR5 also scored higher in tests assessing memory, verbal function and attention.
“When you suffer a stroke, part of your brain dies, severing those cells’ connections with neurons in other regions. That’s why stroke patients often suffer paralysis or lose speech,” Carmichael said. “When CCR5 is missing or blocked, neurons can make new connections and rewire the brain, enabling patients to regain some lost function.”
The next step will be to launch a clinical trial testing the effectiveness of the drug maraviroc on stroke patients with the CCR5 gene.
According to Carmichael, “This is the first time that a human gene has been linked to a better recovery from stroke. Our discovery offers exciting potential for improving patients’ health and enhancing their quality of life.”