Blocking the CCR5 receptor on neurons enhanced the recovery from stroke and traumatic brain injury in animal studies, and patients with the delta32 mutation in CCR5, which renders the receptor nonfunctional, showed better recovery after mild to moderate stroke in the TABASCO clinical trial.
The findings, which were published in the Feb. 21, 2019, issue of Cell, mark the first description of a role for CCR5 in neurology, as well as the first human gene to impact stroke recovery. To date, the clinical attention on CCR5 has been in HIV infection, where the virus uses it as a co-receptor when it enters helper T cells.
"Berlin patient" Timothy Ray Brown became the first known person to be cured of HIV infection after he received a bone marrow transplant from a donor with the delta32 mutation, and the FDA-approved Selzentry (maraviroc) targets the CCR5 receptor.
Given its role and clinical targeting in HIV infection, the CCR5 receptor may offer a readily translatable approach to treating stroke patients – a group that is in dire need of better treatment options.
"It's a hugely prevalent disease," Thomas Carmichael told BioWorld. In the U.S. alone, there are more than 7 million post-stroke patients, making stroke "the leading cause of adult disability."
And there are no drugs.
The only FDA-approved drug for stroke treatment, recombinant tissue plasminogen activator (tPA), needs to be given within 4.5 hours of stroke onset to have an effect. And tPA is only effective in ischemic stroke, which is caused by a blood clot. In hemorrhagic stroke, tPA is contraindicated because the drug can make things worse.
Between those two factors, only a small fraction of individuals who could benefit from tPA receive the drug in practice. Data presented at the International Stroke Conference in 2017 showed that between 2005 and 2011, when tPA had already been approved for a decade, only 4 percent of eligible patients were treated with the drug – though the fraction of patients who were treated did show a steady increase over the six-year study period.
Research into potential stroke treatments often starts from identifying the molecular damage caused by the stroke itself.
Carmichael, who is professor and chair of neurology at the David Geffen School of Medicine at UCLA, and his team approached the problem from a different angle. Their strategy has been to look at the molecular neuroscience of learning and memory for possible processes that could play a role in stroke recovery.
Stroke recovery can look a lot like learning, Carmichael explained. "When you have patients recovering from stroke, it looks like they are learning to walk again."
Those observations prompted his team to suspect that "molecular systems that have a role in memory formation might also help in recovery from stroke."
And those molecular systems are an intensively studied area of neuroscience, meaning that there's plenty of possibilities to look at.
The work now published in Cell had its origins in the screening of so-called smart mouse strains, which have single-gene mutations that improve their learning and memory abilities.
There are 148 such mouse strains, and the researchers screened all of them to see whether any of the mutations affected stroke recovery. And gene knockout of CCR5, Carmichael said, "had one of the strongest effects."
In the studies now published in Cell, the team showed that in animal models, stroke induced the expression of CCR5 on cortical neurons. Inhibiting CCR5 expression with either virally delivered shRNA or Selzentry improved the animals' motor recovery after stroke, and improved cognitive performance after traumatic brain injury (TBI).
Strikingly, the animals showed some improvement in motor performance even when they were treated with Selzentry several weeks after their strokes, suggesting the approach could be useful in the chronic phase of stroke.
Inhibiting CCR5 appeared to aid stroke recovery by enhancing the ability of brain tissue to rewire itself.
"Though the dogma is that you don't form new connections in the brain [in adulthood], there is limited formation of new connections after stroke," Carmichael said. Blocking CCR5 appeared to make it easier for those new connections to form in the tissue adjacent to the stroke cavity. While the cavity is formed by the death of tissue, the tissue adjacent to the cavity survives the stroke, but has a loss of connection.
Carmichael noted that "a number of things lined up in our favor" that will enable the rapid testing of CCR5 antagonism in stroke. Critically, the team was able to look at data from an ongoing observational study, the Tel Aviv Brain Acute Stroke Cohort TABASCO trial, to look for evidence of a role for CCR5 in human stroke patients.
Looking at roughly 400 survivors of mild to moderate strokes who had been genotyped for the presence of the CCR5 delta32 mutation, the team found that the presence of the mutation did not appear to impact either stroke risk or stroke severity, and mutation carriers did no better on functional assessments directly after their strokes.
However, carriers had higher motor, language and sensory recovery both six months and one year after suffering their strokes, and better cognitive function at the one year mark.
Carmichael and his team plan to test whether treating stroke patients with Selzentry will improve recovery; the team has IRB approval for a phase II trial.