Precision Medicine for TBI? NIH Funds Exploratory Study at Barrow

Barrow Neurological Institute has received an R21 grant from the National Institutes of Health (NIH) for a first-of-its-kind study aimed at identifying biomarkers and precise therapeutic targets to predict and prevent contusion expansion in traumatic brain injury.

Contusion expansion describes an enlargement of the injured area of the brain, marked by an increase in swelling and bleeding. This secondary injury raises the risk of death and disability in people with TBI up to fivefold. Although it’s a common challenge faced by neurocritical care physicians, managing contusion expansion doesn’t look much different than it did centuries ago—at least in concept. Therapies include administering salt, cooling the body, draining excess fluid from around the brain, and temporarily removing a portion of the skull.

Right now the guidelines are standardized, but each patient has their own unique type of traumatic brain injury as well as their own unique response.

Ruchira Jha, MD, MSc, Director, Neurocritical Care Program

“Right now the guidelines are standardized, but each patient has their own unique type of traumatic brain injury as well as their own unique response,” said Ruchira Jha, MD, director of the Neurocritical Care Program at Barrow and the principal investigator on the grant. “There are so many different forms of traumatic brain injury. There’s a big difference between someone who falls and hits their head, versus someone who’s in a major car accident, versus someone who has something fall on them at a construction site. And that is just the beginning.”

Dr. Jha and other TBI researchers see an opportunity to shift the paradigm from this reactive, guideline-based approach to a more proactive, precision-medicine approach. She points out that we can think of it like cancer: Breast cancer, for example, comes in many forms. It’s characterized by traits such as the type of tissue from which it arises, whether or not it’s driven by hormones, and what its genetic makeup looks like.

“All of that can change someone’s treatment and prognosis,” Dr. Jha said. “Nobody has cured cancer yet, but it’s light years ahead of traumatic brain injury.”

Step One Involves Much (Cellular) Scrutiny

The first step in developing this precision-medicine approach is understanding what’s happening at the cellular and molecular level in those who experience contusion expansion, compared to those who do not, Dr. Jha said. While TBI experts have identified epidemiological risk factors for this secondary injury, such as the type of bleed and the person’s age, they lack a measurable biomarker—something they can detect in a patient’s biofluids or genetic profile to objectively characterize a person’s risk.

“If someone comes into the hospital with a traumatic brain injury, we cannot undo what has already happened,” Dr. Jha said. “But maybe we can modify their body’s response to that injury to prevent more harm from happening.”

This R21 grant—a mechanism that encourages exploratory research by funding early and conceptual stages of promising studies—will provide Dr. Jha and her collaborators at the University of Pittsburgh with nearly half a million dollars over the course of two years. Her collaborators include Gary Kohanbash, PhD, Patrick Kochanek, PhD, and Dhivyaa Rajasundaram, PhD. The project centers on a channel in the brain known as SUR1-TRPM4 which, as an ion channel, switches electrical currents on and off. Interestingly enough, it’s not present in the normal brain—instead, it responds to injury—and increasing evidence suggests that it’s a major contributor to brain swelling and bleeding progression following a TBI.

“There are things that turn on the channel, things that make the channel open, and things that control it upstream and then happen downstream,” Dr. Jha said. “There are many different pathways that affect this channel, so we’re trying to look at those.” Dr. Jha’s laboratory is collaborating with a multidisciplinary team at the University of Pittsburgh to molecularly endotype pathways of contusion expansion using single-cell and proteomic strategies. In other words, they’re looking at the gene readouts and protein interactions in individual cells within certain cell populations to check for variation.

“Once we understand those cell-based differences, we can try to figure out which are good versus bad, if there is such a thing,” Dr. Jha said. “That may also change with time. It’s possible that in ‘cell A,’ this pathway is important in 24 hours, but by 12 days you really want to shut it down. We don’t know any of that right now.”

Dr. Jha explained that most cellular pathways exist for a reason: They may be important for our daily function or injury response, but then get out of control. “Part of this is trying to understand which cells are helpful for repair and recovery and which are harmful, because then you can have cell-targeted therapy,” she said. “The ultimate goal is to see if we can target therapies to the cells that need it. Again, the first step for that is trying to understand what those cells are doing.”

Fortunately, Dr. Jha and her team already have access to a valuable tool for this work: cerebrospinal fluid from patients with TBI. For many reasons, neurointensivists drain and typically discard this fluid from around the brain as part of the treatment for brain swelling.

“Dr. Jha is an outstanding physician-scientist who conducts true translational bench-to-bedside brain injury research that builds on her clinical expertise as a neurocritical care physician,” said Brad Racette, MD, Chair of Neurology and Senior Vice President at Barrow. “This important project has the potential to impact substantially the lives of millions of people experiencing brain injury and may even inform research into other hemorrhagic brain diseases.”

Next Up: Stitching Together a Framework

Dr. Jha described this R21 grant as one piece of a much larger puzzle that the TBI community is working to solve. This grant looks at neural pathways targeted by a drug known as glyburide. Because this anti-diabetic drug turns on the SUR1-TRPM4 channel, in addition to a channel in the pancreas, it’s being studied by other researchers for use in TBI. While glyburide itself is not the focus of Dr. Jha’s study, her work could help address knowledge gaps in how this drug affects those pathways, as well as inform patient selection for clinical trials.

“Can we hone that drug to specific cell types, specific patients, specific time points?” She posited. “Is that any better than just giving the drug to everybody? We have a ways to go, but I hope we can better identify who to treat and how to treat, and treat them in a way that is less toxic and can improve their disability and survival.”