Polynitroxylated Pegylated Hemoglobin for Traumatic Brian Injury Resuscitation

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 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 hemoglobin as the protein center provides oxygen delivery capabilities the pegylation moieties of PNPH provide hyper colloid properties important to stabilizing hemodynamics during hypotension and 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 hemoglobinandapos 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 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