Traumatic brain injury (TBI) is a leading cause of morbidity and mortality especially when complicated by secondary insults such as hypotension. Vulnerability of TBI patients to hypotension is well recognized and identifies a key need for new approaches. The goal of this proposal is to develop to IND a neuroprotective, hyper-colloid, oxygen therapeutic, polynitroxylated pegylated hemoglobin (PNPH), for pre-hospital resuscitation in the setting of TBI complicated by hypotension. In a 4-year collaboration between Safar Center for Resuscitation Research and SynZyme Technologies funded by the US Army, previous screening of several solutions based on the strategy of using proteins with covalently linked antioxidant nitroxide moieties produced preliminary data suggesting exciting potential for one such agent, PNPH. PNPH has three components contributing to its unique therapeutic activities: 1) hemoglobin as the protein center provides oxygen delivery capabilities 2) the pegylation moieties of PNPH provide hyper-colloid properties important to stabilizing hemodynamics during hypotension, and 3) the nitroxide moieties of PNPH not only improve the safety of cell-free hemoglobin but also provide anti-oxidant/anti-inflammatory and neuroprotective activities. For decades, attention has focused solely on hemoglobin's ability to carry oxygen. In the case of TBI, it is essential that the treatment not only delivers oxygen but also protects neurons. Polynitroxylation converts pro-oxidant hemoglobin into a neuron-protective oxygen carrier, which is an ideal candidate for the proposed therapy. Preliminary studies of PNPH, prepared by polynitroxylation of carboxy (CO) bovine pegylated hemoglobin are presented. In vitro studies suggest that PNPH is a unique hemoglobin with neuroprotective rather than neurotoxic properties. Similarly, in vivo studies show that this PNPH functioned as a small volume resuscitation solution that maximized hemodynamic stability, survival and brain tissue oxygen levels while minimizing neuronal death, after TBI plus HS in mice and outperformed the current standard of care for civilian and military pre-hospital TBI resuscitation. In the phase I of this translational program, quality controlled PNPH will be evaluated to determine product specifications, efficacy in functional outcome and preliminary toxicology. This will set the stage for a pre-IND meeting to obtain FDA guidance. In phase II, production will be scaled up and requisite CMC and FDA required GLP toxicology and safety testing will be performed in preparation for IND submission at the end of the grant period.

Public Health Relevance

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in both civilian and military settings. Secondary insults, such as polytrauma with hemorrhagic shock (HS) are common, especially in cases of severe TBI, and have a devastating impact on outcome. Vulnerability of brain-injured patients to hypotension and brain edema with the current standard of care is well recognized and identifies a key need for new approaches. This application proposes to bring to IND a therapeutic, polynitroxylated pegylated hemoglobin (PNPH), which has been shown to be a unique neuroprotective hemoglobin that functioned as a small volume resuscitation solution that maximized hemodynamic stability, survival and brain tissue oxygen levels while minimizing neuronal death, after TBI plus HS in mice and outperformed the current standard of care for civilian and military pre-hospital TBI resuscitation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Business Innovation Research (SBIR) Cooperative Agreements - Phase II (U44)
Project #
5U44NS070324-04
Application #
8666673
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Hicks, Ramona R
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$971,351
Indirect Cost
Name
Synzyme Technology, Inc.
Department
Type
DUNS #
036552925
City
Irvine
State
CA
Country
United States
Zip Code
92618
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Bell, Michael J; Adelson, P David; Hutchison, James S et al. (2013) Differences in medical therapy goals for children with severe traumatic brain injury-an international study. Pediatr Crit Care Med 14:811-8
Bell, Michael J; Kochanek, Patrick M (2013) Pediatric traumatic brain injury in 2012: the year with new guidelines and common data elements. Crit Care Clin 29:223-38
Brockman, Erik C; Bayýýr, Hulya; Blasiole, Brian et al. (2013) Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. J Cereb Blood Flow Metab 33:1457-64