Polynitroxylated Pegylated Hemoglobin for Traumatic Brian Injury Resuscitation

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$600,000.00
Award Year:
2011
Program:
SBIR
Phase:
Phase I
Contract:
1U44NS070324-01A1
Agency Tracking Number:
U44NS070324
Solicitation Year:
2011
Solicitation Topic Code:
NINDS
Solicitation Number:
PAR08-235
Small Business Information
SYNZYME TECHNOLOGY, INC.
1 TECHNOLOGY DR, B-115, IRVINE, CA, 92618-
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
036552925
Principal Investigator:
CARLETON HSIA
(949) 453-1072
cjchsia@yahoo.com
Business Contact:
FRANCES THOMPSON
(949) 453-1072
fthompsonsynzyme@yahoo.com
Research Institution:
Stub




Abstract
DESCRIPTION (provided by applicant): 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 PNPHis 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 levelswhile 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.

* information listed above is at the time of submission.

Agency Micro-sites

US Flag An Official Website of the United States Government