Truth really can be stranger than fiction, especially when it concerns zombies.
Yes, zombies. Those not-alive-but-not-completely-dead creatures typically portrayed wreaking havoc and leaving chaos in their wake, regardless of whether they shuffle around (“The Walking Dead”) or move with shocking swiftness (“World War Z”). But zombies are fiction. It’s not as though you’d see them in a scholarly journal turned popular magazine like National Geographic…right?
Wrong. Miranda Orr, PhD, associate professor of gerontology and geriatric medicine at Wake Forest University School of Medicine and Research Health Scientist at the W.G. (Bill) Hefner Salisbury Department of Veterans Affairs Medical Center, has appeared twice in National Geographic and in numerous other publications for her research into senescent – or “zombie” – cells. Senescent cells are ones that stop multiplying and functioning normally but don’t die off, much like zombies. Instead, they hang around and secrete toxic chemicals, which disrupt the normal function of other cells.
Research by Orr in 2018 showed these zombie cells accumulated in mouse models of Alzheimer’s disease, creating inflammation and contributing to brain cell loss and memory impairment. This work was the first to show that clearing senescent cells with senolytics, a class of drugs that remove senescent cells while leaving healthy cells intact, stopped Alzheimer’s disease progression. Her subsequent research identified the abundance of zombie cells in human Alzheimer’s disease brains. They found approximately 2% of brain cells to be senescent, and the study identified new biomarkers that have potential to be used in clinical trials.
Orr’s team has translated these findings to clinical trials. Their first-in-Alzheimer’s-disease-patients Phase 1 trial, published in the Sept. 7, 2023, edition of Nature Medicine, reported a favorable safety profile, presence of senolytics in the brain and modest, but promising, movement in Alzheimer’s disease biomarkers in the cerebrospinal fluid. Today, Orr is conducting a Phase 2, multisite, placebo-controlled clinical trial to see if senolytics can help slow or halt disease progression. The Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD) study is currently recruiting participants.
|“We see new things almost every week in the lab. Things are always evolving and changing. We have received funding to pursue different avenues, one of which is trying to figure out why these cells become zombie cells to start with, and what happens if we remove them earlier in the lifespan versus later?” - Miranda Orr, PhD, associate professor of gerontology and geriatric medicine|
Current challenges and looking ahead
“Recruiting is very challenging,” says Orr, even though more than 6 million Americans have Alzheimer’s disease. SToMP-AD currently involves MRIs, PET scans and lumbar punctures, so participants need to be within easy travel distance from a medical center. She is hopeful that the clinical care combination of Atrium Health and Advocate Aurora Health that formed Advocate Health will open up avenues for broader participation from the Charlotte area and in the Midwest.
Orr believes that her future trials should have a wider reach, thanks to data currently being gathered to validate blood biomarkers
“We’ll have information from this trial that has matched data from brain imaging to what’s happening in participants’ spinal fluid to what’s happening in their blood,” says Orr. “In the past few years, that area of study has just exploded, and blood biomarkers are very reliable.”
|Orr’s research was the first to show that clearing senescent “zombie” cells with senolytics, a class of drugs that remove senescent cells while leaving healthy cells intact, stopped Alzheimer’s disease progression. Her subsequent research identified the abundance of zombie cells in Alzheimer’s disease brains and identified new biomarkers that have potential to be used in clinical trials.
And unlike cerebrospinal fluid, blood can be drawn in any lab or doctor’s office. That leads to the possibility of outreach into community settings and rural or underserved areas – areas that are home to many older Americans experiencing cognitive decline who would be interested in helping find answers for future generations.
Finding answers … and more questionsThose answers are needed. The Alzheimer’s Association estimates that by 2050, the number of people 65 and older with Alzheimer’s will grow to about 12.7 million – nearly double the number today. That means clinical trials like Orr’s are more important than ever.
“The good news is there is a lot of active research and therefore a lot of clinical trials to choose from,” says Orr. These trials include drug trials, behavioral interventions (for example, exercise) and dietary trials. And each trial has its own criteria for participating, she says, including the SToMP-AD trial. People interested in learning more about eligibility for SToMP-AD can see a full list of inclusion and exclusion criteria at ClinicalTrials.gov.
In addition to participants enrolling themselves, physicians can refer patients they think would be a good fit for the trial. Typically, those turn out to be good candidates, and Orr welcomes such referrals.
And even while the trial is ongoing, the research continues to grow and expand.
“We see new things almost every week in the lab,” says Orr. “Things are always evolving and changing. We have received funding to pursue different avenues, one of which is trying to figure out why these cells become zombie cells to start with, and what happens if we remove them earlier in the lifespan versus later?”
With so many questions, the need for research and for clinical trials continues, too. Targeting zombie cells with senolytics could open new horizons for the treatment of Alzheimer’s disease, possibly in tandem with other therapies.
“We think combination therapy is going to be very important,” says Orr. “Combining senolytics with amyloid-lowering, tau-lowering (drugs), changing metabolism, lifestyle interventions…there’s a lot of different options.”