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  1. Advancing Regulatory Science

Phase 1: Development of diagnostic biomarkers for determination of traumatic brain injury

CERSI Collaborators: Maureen A. Kane, Ph.D., Marta M. Lipinski, Ph.D., Jace W. Jones, Ph.D., Chinmoy Sarkar, Ph.D.

FDA Collaborators: CDER OND: Abbas Bandukwala, CDR, USPHS, Jeffrey Siegel M.D., Chris Leptak M.D., Laura B. Jaeger Ph.D., Shila Nkah, Beth Walton

Project Start Date: September 2019

Project End Date: September 2022

Regulatory Science Challenge

More than 1.7 million new cases of traumatic brain injury (TBI) occur annually in the United States. TBI is a sudden injury that causes damage to the brain that may happen when there is a blow, bump, or jolt to the head. People with a TBI could die from this injury; many have a high likelihood of having a long-term disability. TBI has also been proposed as a major risk factor for the development of neurodegenerative diseases (diseases affecting many of the body's activities, such as balance, movement, talking, breathing, and heart function). Currently, TBI is diagnosed by physicians using clinical outcome assessments (i.e., measures that describe or reflect how a patient feels, functions, or survives) which can be hard to use depending on the condition of the patients. For example, patients may be unconscious or unable to open their eyes because of injury to their face. There is a lack of minimally invasive, quantitative diagnostic biomarkers to help diagnose TBI. Diagnostic biomarkers are used to detect or confirm presence of a disease or condition of interest or to identify individuals with a subtype of the disease.) This study was aimed at developing biomarkers to be used in clinical trials to help develop new drugs to treat TBI. These biomarkers may help with the diagnosis and assessment of the severity of the TBI which can then help enroll patients into drug clinical trials for TBI.

Project Description and Goals

The goal of this project was to determine the utility of specific lipids (fats in the blood) to serve as minimally invasive diagnostic plasma biomarkers. This project studied animals (mice) and human patients to evaluate new TBI biomarkers. The study involved applying a blunt force injury to each mouse’s head to assess the change in the biomarker at mild, moderate, and severe levels of injury. A calibrated machine was used to ensure each mouse received the same blunt force to the head. Used along with other clinical factors, the plasma biomarker level identified and possibly stratified (sort into different levels of injury) patients with TBI according to the severity of their injury. These data allow for an objective measurement of TBI according to the measurement of specific lipids in patient plasma that is collected when patients are admitted to the hospital.

Research Outcomes/Results

A mouse study was used to characterize and understand the biomarkers observable during a TBI event. The mouse model applied the same level of injury to each mouse to assess the variability of the biomarker. The model also correlated the biomarker to physical and cognitive functional outcomes like a balance beam test, or memory test for the mouse. The mouse model was also used to determine the biomarker levels at mild, moderate, and severe injury. Another test confirmed that the biomarker levels changed only during TBI and not with other injuries to the body, like muscle or skeletal injuries. The biomarker levels also seemed to be able to distinguish between mild, moderate, and severe TBI. Based on the results of the animal study, a pilot study using 10 human blood samples from confirmed TBI cases were evaluated. These blood samples were taken within 24 hours of the TBI. Six blood samples were from confirmed severe TBI and 4 samples were from confirmed moderate TBI. The results from this small pilot study confirmed that there was a notable difference in biomarker levels between severe and moderate TBI. The pilot study helped translate the mouse model and data to humans. The pilot study also confirmed that the biomarkers correlate with TBI and the severity of TBI.

Research Impacts

Based on these results, a larger human study will be conducted to better correlate these biomarkers in mild, moderate, and severe TBI. This study will develop biomarkers that can be used in clinical trials to develop new drugs to treat TBI. These biomarkers may help with the diagnosis and assessment of the severity of the TBI which can then help enroll patients into drug clinical trials for TBI.

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