VCU study suggests brain waste clearance may relieve sickle cell disease pain

By Jeff Kelley

A year ago, Casey Grey didn't know much about sickle cell disease. An adjunct professor and postdoctoral researcher in Virginia Commonwealth University's College of Engineering, Grey studies the brain's glymphatic system, a cerebrospinal fluid-driven network that clears metabolic waste and inflammatory molecules from the brain during sleep.

His research has focused on using targeted light and sound stimulation to enhance this clearance pathway, with potential applications to neurological diseases and brain injury. Blood-based sickle cell disease wasn't on his radar.

"I always thought of it as a blood disease, not a brain condition," said Grey, Ph.D. "The red blood cells sickle, they block blood vessels, and that's where the problems occur. But I didn't realize how much of the disease involves the brain."

Finding an unexpected connection

That changed when Grey attended a presentation given by VCU pharmacologist Aron H. Lichtman, Ph.D., whose School of Medicine laboratory studies sickle cell disease in collaboration with physician-scientists including Wally R. Smith, M.D., director of the VCU Adult Sickle Cell Program, and Daniel Sop, Ph.D., a senior research scientist in the program.

One set of images caught Grey's attention: brain scans of healthy individuals compared to brain scans of people with sickle cell disease. Unlike healthy brains, where blood flow naturally declines with age, patients with sickle cell disease experience chronically elevated cerebral blood flow that continues to increase over time. Those increases are associated with chronic pain and cognitive impairment.

"I looked at that image and thought, 'Wow,'" Grey said. "The blood vessels were really definitely disrupting glymphatic flow."

That realization became the foundation for a new collaboration among engineers, pharmacologists and physician-scientists across VCU.

Testing a new idea

Grey led the team's pilot study, published in July in the Journal of Sickle Cell Disease, which found that one hour of daily 40 Hertz light and sound stimulation dramatically reduced chronic pain behaviors in a humanized mouse model of sickle cell disease. Previous research has shown this type of sensory stimulation increases the release of signaling molecules that help restore healthy blood vessel function and improve glymphatic clearance throughout the brain.

After six weeks of treatment, mice with sickle cell performed similarly to healthy controls on measures of mechanical sensitivity and grip strength, two well-established indicators of chronic pain. When treatment stopped, those improvements gradually disappeared, suggesting the therapy works by continually addressing an underlying biological process rather than by permanently altering the disease itself.

Just as significant as the findings themselves is what they may reveal about the disease.

Grey and his colleagues propose that chronic anemia in sickle cell disease causes blood vessels in the brain to remain abnormally dilated. Those enlarged vessels may compress the tiny fluid-filled channels surrounding them, called perivascular spaces, preventing cerebrospinal fluid from washing away metabolic waste through the brain's glymphatic system.

The resulting buildup of inflammatory molecules could help explain why many patients experience chronic pain, cognitive decline and neurological complications that cannot be fully explained by blocked blood vessels alone.

"We think we've uncovered a major mechanism of pain in sickle cell disease," Grey said. "We're not curing it, and we're not changing the red blood cells. What we're trying to do is interrupt the brain's pathological response to the disease."

Grey was encouraged by how well the noninvasive approach worked.

"Light and sound - nothing invasive, no drugs - essentially normalized these animals," he said. "It outperformed every pharmacological treatment we've given these mice and can be administered with inexpensive, widely available equipment."

From discovery to commercialization

The study also strengthens Grey's commercialization efforts underway through VCU TechTransfer and Ventures.

Thomasine Isler, a licensing manager who works closely with Grey on technologies with commercialization potential, said the study provides the evidence that potential industry partners have been waiting to see.

"The findings in the sickle cell research start to show that there is a concept here that is backed by data and science," Isler said. "Now we can demonstrate that there's published evidence supporting the technology that we hope to someday commercialize."

Grey's team has also secured additional funding from the Children's Hospital Research Institute to investigate the effects of 40 Hz therapy in premature infants, another neurologically at-risk patient population. The next phases of research will test whether impaired glymphatic function can be directly measured in sickle cell disease, determine exactly how 40 Hz stimulation restores normal brain physiology and begin expanding this work to human sickle cell disease patients at VCU Health.

The treatment could also potentially treat respiratory disease, cardiovascular disease, sleep apnea and other conditions where chronically low blood oxygen causes blood vessels to stay dilated.

For now, Grey sees the work as one piece of VCU's broader effort to understand and treat sickle cell disease. "We already have therapies that target blood cells," he said. "What I hope this becomes is the missing link in sickle cell disease treatment. If we can pair existing therapies with something that protects the brain, maybe we can completely normalize these patient's lives."

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