Posted October 05, 2016
Charles Cox, Jr. M.D., University of Texas Health Science Center at Houston

Severe traumatic brain injury (TBI) affects upwards of 50,000 people in the United States per year and contributes to half of all trauma deaths. Unfortunately, there are no effective restorative or reparative treatments to reverse the primary injury associated with the TBI. Furthermore, secondary brain injury after TBI, which manifests clinically as increased blood-brain barrier permeability and cerebral edema, have been directly linked to increased intracranial pressure and early morbidity and mortality after TBI. These neurological derangements often evolve after the moment of impact and, even if carefully monitored, can lead to brain damage and increase mortality. These secondary, or follow-on effects, of severe TBI are concerning and contribute significantly to the shockingly high 33% mortality rate. There is a great unmet need to treat, prevent, and mitigate acute such neurological injuries, especially in our Service member population. Compared to their civilian peers, active duty and reserve Service members are at increased risk for sustaining a TBI. The high rate of TBI in our Service member population directly impacts the health and safety of individual Service members and subsequently the level of unit readiness and troop retention.

Dr. Charles Cox, of the University of Texas Health Science Center at Houston, has set out to improve outcomes in severely injured TBI patients. He and his colleagues designed and implemented a clinical trial to evaluate whether the intravenous reinfusion of a patient's own progenitor cells was safe and if it improved functional outcomes. In the past decade, there has been growing support in the literature regarding the use of various progenitor cell types to treat acute neurological injuries such as TBI and stroke. In this trial, the TBI patients receiving the intervention received a single intravenous infusion of autologous transplantation of bone marrow mononuclear cells (BMMNC) within 36 hours of their TBI. Dr. Cox and his collaborators hypothesized that harvesting and collecting BMMNCs from patients would be safe and that reinfusion would improve their functional outcomes compared to TBI patients who did not receive the transplantation infusion. The study results supported the primary safety outcome that BMMNC harvest and autologous infusion after TBI is a safe procedure; Dr. Cox and his colleagues found no safety issues and/or serious adverse events related to the harvest or infusion of BMMNC in the TBI patients.

Although standardized outcome scores failed to demonstrate statistical significance between the control patients and BMMNC infusion patients (i.e., treatment groups), there were several strong correlations between structural preservation and functional outcomes in the TBI patients receiving the infusion. The data from the trial indicate that there was a trend toward white matter preservation in the treatment groups versus the control group, as well as a higher average fractional anisotropy and lower mean diffusivity in the treatment groups versus the control group. This is significant because higher fractional anisotropy and lower mean diffusivity correlate with improved fiber tract integrity, indicating greater structural preservation in the BMMNC infusion patients. Furthermore, inflammatory biomarkers IL-I� and IL-10 were significantly lower in the treatment group when compared to the control group and the inflammatory biomarkers TNF-a INF-?, and IL-6 were also lower in the treatment group, but not enough to label the observation as statistically significant. The overall trend of decreased inflammation, as evidenced in Dr. Cox's inflammatory biomarker analysis, suggests that BMMNC infusion after TBI may help stifle the brain's secondary inflammatory response to injury and thus exert a neuroprotective effect, helping to improve memory and cognitive function in TBI patients.

Due to the success of his initial clinical trial, Dr. Cox has secured follow-up funding from the Department of Defense to perform a Phase 2b clinical trial. The intervention is a cellular therapy using BMMNCs (investigational new drug BB-12620) and determine definitively if these cells, harvested and isolated from a patient's own bone marrow, can be infused to control the brain swelling after TBI. Dr. Cox hypothesizes that after severe TBI in adults, intervention with BB-12620 will aid in the preservation of global grey matter and white matter as measured by MRI (magnetic resonance imaging) scans. Dr. Cox also plans to explore whether the structural findings he uncovers correlate with a dampening of the neuroinflammatory response to TBI. If positive, these data will provide the biological rationale/human proof-of-concept for a Phase 3 study, potentially defining biomarkers for activity. Dr. Cox is hopeful that cellular therapies, such as intervention with BB-12620, will help repair and restore damage incurred after TBI and also be used as a foundation for therapies intended to treat and/or prevent TBIs.

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