In search of blood biomarkers that could aid diagnosis and prognosis of patients with traumatic brain injury or who have a risk of stroke, Emory University researchers are planning two parallel biomarker studies using samples from participants enrolled in large multi-center clinical trials.
The first project, funded with a $1.47 million, four-year grant from the National Institutes of Health, is called “Biomarkers of Ischemic Outcomes in Intracranial Stenosis,” or BIOSIS, and is using samples from the SAMMPRIS trial, a randomized multi-center test of stenting as a treatment for intracranial stenosis. Working with two Emory laboratories, the trial is investigating four markers — three inflammatory proteins, as well as endothelial progenitor cells — that have shown promise in earlier work.
The second study, “Biomarkers of Injury and Outcome in ProTECT III," or BIO-ProTECT, is funded by a $2.6 million, five-year NIH grant and is analyzing samples from patients enrolled in the ProTECT III trial; an Emory-led multi-center study of progestin to treat traumatic brain injury. In BIO-ProTECT, the Emory team has contracted Banyan Biomarkers to do the proteomic analysis. The Alachua, Fl.-based company will analyze blood samples from TBI patients for four different protein markers.
According to Michael Frankel, an Emory neurologist and principal investigator on the two biomarker studies, molecular information would offer opportunities for more accurate prognosis and potentially more effective treatment for both conditions.
Intracranial stenosis is one of the leading causes of stroke worldwide and is particularly frequent in African and Asian populations, according to Frankel. The goal of the BIOSIS study linked to the stenting trial is to provide clinicians with a tool that could help risk stratify patients, he told PGx Reporter. "If you come to me and tell me you had a small stroke or a [transient ischemic attack], I'd like to be able to tell you … the likelihood of you having another stroke," he said.
Additionally, endothelial progenitor cells may potentially be markers from which new treatments can be developed. "It is possible to harvest one's own progenitor cells and inject them later … Cardiologists are doing this in heart diseases, but it hasn't really been done in the brain yet," Frankel noted.
In the second trial, Frankel hopes to evaluate whether the severity of traumatic brain injury can be measured by protein signatures in the blood.
"When the brain is injured, proteins are released into the bloodstream," he said. "A primary question asked for years, but not adequately answered, is,' Can the proteins tell us how severe the brain injury is?"
Since brain injury patients may be treated in a number of ways, this is an important question. "If we have a blood test that can complement what we do at the bedside and what we do with CT, it could really help us from a prognosis point of view to determine who is at high risk for a bad outcome and who is not," he said.
"Also important is the idea that we might be able to monitor the effects of progesterone treatment by measuring the proteins in the blood that reflect the amount of brain injury," he added. "We might have a window into the early effects of progesterone in terms of its ability to suppress the release of those proteins from the brain as an indicator that the drug is working."
But before all that can be accomplished, researchers must first measure and validate the biomarkers of interest.
According to Frankel, the SAMMPRIS trial was recently closed after enrolling about 60 percent of its intended subjects, after investigators found that stenting did not appear to reduce the risk of another stroke. The researchers published a report of their initial findings in the New England Journal of Medicine this month. Despite the fact that the main trial has been stopped, Frankel and his colleagues will evaluate patient samples from this trial for biomarkers and follow the patients for at least another two years.
The biomarkers the team has targeted for the BIOSIS study — hsCRP, PAI-1, E-selectin, and endothelial progenitor cells — are "based on preliminary data that suggests that the population of endothelial cells as well as inflammatory protein markers likely represent the clue into the future risk of having another stroke," Frankel said.
Though stenting didn't prove itself in the trial cohort as a whole, Frankel is hoping these markers will reveal more about who should or shouldn’t be stented. "Maybe there is a subgroup who should, and this type of blood test could help us pick them out," he said.
Additionally, since EPCs are the body's repair mechanism for the lining of the blood vessels, they have potential as a treatment in themselves. "The cells connect to each other to make the endovascular surface," according to Frankel.
Though researchers have begun to investigate EPCs as a treatment in heart disease, no one has yet tried to do the same in the brain, he said.
ProTECT III — the trial from which Frankel and his colleagues are using samples to conduct the second brain injury biomarker study — is only about one-fourth complete and is aiming to enroll 1,140 subjects in 25 to 30 participating centers.
Frankel noted that the concept of treating brain injury patients with progesterone was based on work conducted by Emory neuroscientist Donald Stein, "who worked early on with animal models and found that pseudopregnant rats were having a much better recovery from experimental brain injury as a result of the high progesterone levels."
This eventually led to a pilot study in humans, led by Emory's David Wright, which showed a promising 50 percent reduction in mortality — enough to move forward with the larger ProTECT III trial, which is evaluating intravenous injections of progesterone given within the first four hours of traumatic brain injury against placebo.
Much as he did for the SAMMPRIS project, Frankel said he proposed a parallel study that would collect blood samples for biomarker analysis hoping to take advantage of the cohort for the identification of possible prognostic markers.
As with BIOSIS, the Emory team chose target protein markers for BIO-ProTECT — UCH-L1, SBDP150, GFAP, and S100B — based on promising early research. Frankel said the four proteins are markers of injury to neurons, injury to the cytoskeletal framework, and axons.
Frankel characterized S100B as a well-known marker, while GFAP is a promising newcomer. SBDP150 and UCH-L1 are both novel, and have spurred the team to work with Banyan Biomarkers investigator Andreas Jeromin, who has done promising preliminary work with these two markers, he said
The team hopes to find signatures that can predict the level of traumatic brain injury and future impairment, and is planning to carefully measure how the levels of these brain injury proteins respond to the progesterone treatment being tested in the clinical trial, an analysis that Frankel said should complement the trial's overall evaluation of the drug's effectiveness.
To monitor and evaluate progesterone, the researchers are collecting blood samples upon patient admission to the ProTECT III trial and at 24 hours and 48 hours. "If [progesterone is] working we should see less of these proteins released," Frankel said.
We hope that will give us some greater insight into how people will be doing down the road and how they will respond to treatment," Frankel said.
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