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Therapeutic for Intracerebral Hemorrhage

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
94056
Program Year/Program:
2009 / SBIR
Agency Tracking Number:
NS064651
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
COGNOSCI, INC.
79 T. W. Alexander Drive RESEARCH TRIANGLE PARK, NC 27709-2076
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2009
Title: Therapeutic for Intracerebral Hemorrhage
Agency: HHS
Contract: 1R43NS064651-01A1
Award Amount: $258,584.00
 

Abstract:

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating and relatively common disease affecting as many as 50,000 people annually in the United States alone. ICH remains associated with poor outcome, and approximately 40 to 50 % of afflicted patients will die within 30 days. Unfortunately, little improvement has been made in the ICH associated mortality rate over the last 20 years. Using the traditional preclinical ICH animals models, clostridial collagenase-induced hemorrhage a nd autologous blood injection, a growing body of literature indicates that specific mitogen activated protein kinase (MAPK) signaling cascades and other signaling pathways become activated following ICH. Activation of the MAPK proteins p38, c-Jun N-termina l Kinase (JNK), and Extracellular signal-Related Kinase (ERK) have been reported and these molecular observations suggest new approaches that can be exploited for development of novel therapies for ICH. Apoliopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its function in cholesterol metabolism, apoE has been demonstrated to play a uniquely important role in modifying the CNS response to injury, and in the case of ICH, a pharmacogenomic effect has been demo nstrated where APOE4 carriers suffer worse outcome relative to their APOE3 counterparts. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti- inflammatory activities. In mechan istic studies we have demonstrated that COG1410, an optimized apoE- based peptide, suppresses phosphorylation and the accompanying activation of MAP kinases including p38, JNK, and ERK. Suppression of MAPK activation is consistent with the observation of r educed inflammation and may reduce the occurrence of neurodegeneration following ICH. Furthermore, we have demonstrated that apoE-mimetic peptides provide direct neuroprotective effects on neurons in vitro by inhibiting the excitotoxic activity of N-Methyl -D-Aspartate (NMDA). Neuroprotective activity was also demonstrated in vivo following oxygen depravation in a perinatal hypoxia model of ischemic injury. We performed an initial evaluation of COG1410 in the collagenase model of ICH and found that COG1410 i mproved outcome as measured by motor function and neuroseverity scores. Based on these observations, we now propose to measure the effect of different doses of COG1410, administered after the hemorrhage, on neurological outcome to determine the optimal dos e. Further, we propose to determine the effect of COG1410 treatment on the phosphorylation status of key MAPK signal transduction proteins following ICH. By completing this work we will obtain proof of principle that will form the basis for preclinical stu dies required to file an Investigational New Drug application with the FDA to initiate human clinical trials for this important orphan indication. PUBLIC HEALTH RELEVANCE: Intracerebral hemorrhage (ICH) is a devastating and relatively common disease affect ing as many as 50,000 people annually in the United States alone. ICH remains associated with poor outcome, and approximately 40 to 50% of afflicted patients will die within 30 days. Unfortunately, little improvement has been made in the ICH associated mor tality rate over the last 20 years. Using the traditional preclinical ICH animals models, clostridial collagenase-induced hemorrhage and autologous blood injection, a growing body of literature indicates that specific mitogen activated protein kinase (MAPK ) signaling cascades and other signaling pathways become activated following ICH. Activation of the MAPK proteins p38, c-Jun N-terminal Kinase (JNK), and Extracellular signal-Related Kinase (ERK) have been reported and these molecular observations suggest new approaches that can be exploited for development of novel therapies for ICH. Apoliopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its function in cholesterol metabolism, apoE has been demonstrated to play a uniquely important role in modifying the CNS response to injury, and in the case of ICH, a pharmacogenomic effect has been demonstrated where APOE4 carriers suffer worse outcome relative to their APOE3 counterparts. Cognosci has recently developed n ovel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti- inflammatory activities. In mechanistic studies we have demonstrated that COG1410, an optimized apoE- based peptide, suppresses phosphorylation and the acco mpanying activation of MAP kinases including p38, JNK, and ERK. Suppression of MAPK activation is consistent with the observation of reduced inflammation and may reduce the occurrence of neurodegeneration following ICH. Furthermore, we have demonstrated th at apoE-mimetic peptides provide direct neuroprotective effects on neurons in vitro by inhibiting the excitotoxic activity of N-Methyl-D-Aspartate (NMDA). Neuroprotective activity was also demonstrated in vivo following oxygen deprivation in a perinatal hy poxia model of ischemic injury. We performed an initial evaluation of COG1410 in the collagenase model of ICH and found that COG1410 improved outcome as measured by motor function and neuroseverity scores. Based on these observations, we now propose to mea sure the effect of different doses of COG1410, administered after the hemorrhage, on neurological outcome to determine the optimal dose. Further, we propose to determine the effect of COG1410 treatment on the phosphorylation status of key MAPK signal trans duction proteins following ICH. By completing this work we will obtain proof of principle that will form the basis for preclinical studies required to file an Investigational New Drug application with the FDA to initiate human clinical trials for this impo rtant orphan indication.

Principal Investigator:

Dale J. Christensen
9197650028
DCHRISTENSEN@COGNOSCI.COM

Business Contact:

Michael P. Vitek
mikevitek@cognosci.com
Small Business Information at Submission:

COGNOSCI, INC.
COGNOSCI, INC. 79 T. W. Alexander Drive RESEARCH TRIANGLE PARK, NC 27709

EIN/Tax ID: 562208520
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No