April 27, 2018
Mayo Clinic is conducting the first clinical trial in the United States of stem cell treatment for intracerebral hemorrhage (ICH). The investigators hope that results of the phase 1 trial, conducted in conjunction with Mayo Clinic's Center for Regenerative Medicine, will lead eventually to therapies that provide neuronal protection or recovery for people with ICH.
"This is cutting-edge research, using cells as drugs to help to repair the damage that occurs in hemorrhagic stroke," says Abba C. Zubair, M.D., Ph.D., a consultant in Pathology at Mayo Clinic in Jacksonville, Florida, and a co-principal investigator of the trial. "We haven't had treatment options that address neuronal recovery or protection of neurons. A regenerative therapy would be highly beneficial."
Intracerebral hemorrhage and external ventricular drain
On the left, the CT image shows an intracerebral hemorrhage (ICH) with external ventricular drain (EVD) in the coronal plane. On the right, the drawing illustrates placement of an EVD in an ICH.
Roughly half of hemorrhagic strokes result in death within 30 days. Current treatment modalities focus on controlling inflammation and providing supportive therapies.
"Although significant advances have occurred in the treatment of stroke, the subset of patients with hemorrhagic stroke haven't benefited as much. We are passionate about raising the level of treatment for ICH closer to our ability to treat patients with ischemic stroke," says William D. Freeman, M.D., a consultant in Neurology at Mayo Clinic's Florida campus.
The stem cell clinical trial targets acute ICH treated within 72 hours of stroke onset. "Our preclinical experiments showed that the effects of treatment aren't as prominent after delay," Dr. Zubair says. "In this clinical trial, we want to target the population that would be most likely to benefit. But in the future, we would hope to study treatment that occurs later."
Participants in the 12-patient trial will be divided into four groups of three patients. Three of the groups will receive allogenic mesenchymal stem cells intravenously, at three different dose levels. The fourth group, composed of patients who require a brain catheter to reduce pressure from hydrocephalus, will have intraventricular delivery of stem cells through a catheter. "In addition to optimal dosage, we want to study the best method of delivery," Dr. Freeman says.
Possible mechanism of action
Mesenchymal stem cells
Mesenchymal stem cells are fibroblast-like and can adhere to plastics in standard culture conditions.
In preclinical experiments, Mayo Clinic researchers demonstrated that mesenchymal stem cells have anti-inflammatory properties and the capacity to rescue injured neurons. In these experiments, neuronal cells were subjected to oxygen-glucose deprivation stress, which resulted in a significant decrease in cell proliferation and an increasing rate of apoptosis, as well as elevated levels of tumor necrosis factor-alpha. Subsequent co-culture of the neuronal cells with mesenchymal stem cells alleviated those effects.
The researchers believe that interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), which are known to be secreted by mesenchymal stem cells, play an important role in stem cells' mechanism of action. "Our laboratory work showed that when IL-6 or VEGF is blocked, the mesenchymal stem cells do not have the positive effects of regenerating neurons and improving their viability," Dr. Zubair says.
The preclinical experiments also demonstrated that mesenchymal stem cells don't need to be in direct contact with injured neurons to exert their regenerative effect — suggesting that stem cells can remotely affect the site of brain injury by releasing factors that permeate the blood-brain barrier. Indeed, while evaluating various methods of delivering stem cells, the researchers found that injection of stem cells directly into the stroke site was less effective than the intravenous or intraventricular approaches.
"We were surprised that direct injection doesn't seem to work," Dr. Zubair says. "But in our preclinical work, both intravenous and intraventricular approaches were effective."
The clinical trial is the culmination of seven years of laboratory work. "One of our core values at Mayo Clinic is integrating basic science into the clinical practice," Dr. Freeman says. "We feel there can be rapid leaps in care to help patients with ICH. Our goal is to improve the welfare of those patients."
For more information
Mayo Clinic. Mesenchymal Stem Cells Therapy in Patients With Recent Intracerebral Hemorrhage. ClinicalTrials.gov.