Department of Defense awards Weil Institute investigators $750,000 to rewrite the rules for traumatic brain injury
Research will provide answers to long-awaited questions about therapeutic potential and deliver proof-of-principle data to test other therapies for TBI.
Contact:
Megan VanStratt, Marketing Communications Director, Weil Institute
vanstrat@umich.edu
ANN ARBOR, MI – With more than a million cases of traumatic brain injury (TBI) and 500,000 people left permanently disabled each year in the US alone, TBI has significant societal impact on both military and civilian populations. Despite significant efforts to find therapies capable of improving patient outcomes, there are still no FDA-approved neuroprotective therapeutics for patients with TBI. One of the major hurdles facing researchers is the inability of many drug candidates to cross the blood brain barrier (BBB), a network of blood vessels and tightly connected cells that prevents most molecules from crossing from the bloodstream into the brain tissue. A promising strategy being developed by two Weil Institute members, Dr. Colin Greineder, Assistant Professor of Emergency Medicine and Pharmacology, and Dr. Peter Tessier, Albert M. Mattocks Professor of Pharmaceutical Sciences and Chemical Engineering, was recently awarded a $750,000 grant by the Department of Defense to help address this challenge.
Figuring out how to get antibodies across the blood-brain barrier is one of the most important challenges in contemporary neuropharmacology.
“Clinical trials for TBI have focused on small molecule drugs which naturally cross the BBB”, said Dr. Greineder. “In contrast, our work focuses on monoclonal antibodies, large proteins which hold great potential for the treatment of brain disorders but don’t normally penetrate into brain tissue. Figuring out how to get antibodies across the BBB is one of the most important challenges in contemporary neuropharmacology, and one that will eventually lead to life-changing therapeutics for TBI and other brain injuries.”
The team’s proposed project uses their bispecific antibody shuttle technology, which engages CD98hc, a protein involved in transporting amino acids across the BBB. In this case, the antibody that will be shuttled into the brain tissue is one that mimics the function of brain derived neurotrophic factor (BDNF), a naturally occurring growth factor that has been linked to recovery from TBI. BDNF itself was once felt to have therapeutic potential but has never been investigated in clinical trials because of its inability to cross the BBB.
In preliminary work, done in healthy mice, Greineder, Tessier, and colleagues found that a single intravenous dose of their bispecific antibody shuttle provides several days of BDNF-like signaling in the brain. This work has been published online as a pre-print and is currently in press at Cell Chemical Biology. With the new funding from the DoD, the team will be able to test the antibody shuttle in two models of TBI – one established at the University of Michigan and a model of blast-induced TBI developed at the Walter Reid Army Institute of Research.
"The funding from the Grand Challenge was critical to the early phase of development of our BBB shuttle technology. We are incredibly grateful for the support of the Massey Foundation and the Weil Institute and for their assistance in preparing our DoD proposal"
Colin Greineder, MD, PhD
Assistant Professor, Emergency Medicine and Pharmacology
University of Michigan, Michigan Medicine
“To date, our focus has been on understanding the transport mechanism and the ability of shuttled antibodies to reach cellular targets once in the brain tissue,” said Dr. Greineder. “The DoD grant gives us the opportunity to extend this work to clinically relevant disease models and to determine the therapeutic potential of boosting the BDNF signaling pathway following TBI.”
The project was originally funded by the Weil Institute’s Massey TBI Grand Challenge, a funding avenue for multidisciplinary critical care research teams that supports the development of diagnostic, device, therapeutic or health IT solutions addressing the initial ‘golden hours’ of care after severe traumatic brain injury.
“The funding from the Grand Challenge was critical to the early phase of development of our BBB shuttle technology,” said Dr. Greineder. “We are incredibly grateful for the support of the Massey Foundation and the Weil Institute and for their assistance in preparing our DoD proposal.”
Indeed, the team was alerted to the DoD funding opportunity by Weil’s Proposal Development unit and worked with them to prepare the application.
“The proposal would not have happened without the support of the Weil Institute and the research administrators from the Department of Emergency Medicine,” said Dr. Greineder. “They were familiar with the funding mechanism and helped ensure that we met all of the unique requirements of the DoD process.”
According to the Department of Defense and the CDC, TBI is now the most common injury suffered by warfighters. If successful, this therapy could be easily carried by medics on the battlefield and could be quickly administered during the acute and post-acute phases for casualties suffering from TBI. More specifically, this therapy will save brain cells and reduce the cognitive and behavioral impairments caused by TBI, representing a major breakthrough in TBI research.
About the Weil Institute, formerly MCIRCC
The team at the Max Harry Weil Institute for Critical Care Research and Innovation (formerly the Michigan Center for Integrative Research in Critical Care) is dedicated to pushing the leading edge of research to develop new technologies and novel therapies for the most critically ill and injured patients. Through a unique formula of innovation, integration and entrepreneurship that was first imagined by Weil, their multi-disciplinary teams of health providers, basic scientists, engineers, data scientists, commercialization coaches, donors and industry partners are taking a boundless approach to re-imagining every aspect of critical care medicine. For more information, visit weilinstitute.med.umich.edu.