Mather

HEALTH CARE AND OTHER FACILITIES

PREVENTION AND MITIGATION OF ACUTE TRAUMATIC COAGULOPATHY AND BLEEDING - PROJECT SUMMARY/ABSTRACT HEMATHERIX IS DEVELOPING SUPERFVA FOR THE TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY (ATC). MORTALITY RATES WITH TRAUMATIC HEMORRHAGE OFTEN EXCEED 40%, EXPOSING AN UNMET CLINICAL NEED FOR TARGETED DRUG DEVELOPMENT. ATC DEVELOPS EARLY ON AS THE CONSEQUENCE OF SEVERE TRAUMA AND SHOCK, PRIOR TO ADDITIONAL IATROGENIC EFFECTS. ATC IS DISTINCT FROM OTHER COAGULOPATHIES AND IS CHARACTERIZED BY THE SELECTIVE DIMINISHMENT OF FACTOR V, FACTOR VIII, AND FIBRINOGEN LEVELS DUE TO THE EXAGGERATED ACTIVATION OF THE PROTEIN C AND FIBRINOLYTIC PATHWAYS FOLLOWING VASCULAR DISRUPTION DUE TO TRAUMA AND SHOCK. THE PRESENCE OF ATC IS ASSOCIATED WITH UNCONTROLLABLE BLEEDING AND INCREASED TRANSFUSION REQUIREMENTS, ESPECIALLY DURING EMERGENCY SURGERY, RESULTING IN INCREASED RISKS OF ORGAN FAILURE AND DEATH. ACTIVATED FACTOR V (FVA) IS AN ESSENTIAL CO-FACTOR IN THE PROTHOMBINASE COMPLEX, ENHANCING THE RATE OF THROMBIN GENERATION APPROXIMATELY 10,000-FOLD, BUT IS READILY INACTIVATED BY ACTIVATED PROTEIN C (APC). SUPERFVA IS A STABLE ENGINEERED VARIANT OF THE ACTIVATED COAGULATION COFACTOR FACTOR V AND POSES A UNIQUE TARGETED THERAPY TO PREVENT AND CORRECT ATC. KEY FEATURES OF SUPERFVA ARE ITS RESISTANCE TO INACTIVATION BY APC DUE TO MUTATION OF THE APC CLEAVAGE SITES (ARG506/306/679GLN) AND ITS INCREASED SPECIFIC ACTIVITY AND STABILITY DUE TO AN ENGINEERED DISULFIDE LINK BETWEEN THE A2 AND A3 DOMAINS. THE UNIQUE CHARACTERISTICS OF SUPERFVA DIFFERENTIATE IT FROM EXISTING PROHEMOSTATIC AND OTHER EXPERIMENTAL ANTI-APC APPROACHES IN DEVELOPMENT AND MAKES SUPERFVA INIMITABLY POSITIONED AS A TARGETED STRATEGY FOR ATC. DATA IN MURINE MODELS OF ATC SUPPORT THE CONCEPT THAT APC IS A MAJOR INSTIGATOR OF ATC. WE RECENTLY REPORTED THAT SUPERFVA EFFICIENTLY PREVENTED ATC WHEN GIVEN PROPHYLACTICALLY AND CORRECTED ATC WHEN GIVEN THERAPEUTICALLY IN 2 MURINE MODELS WHERE ATC WAS INDUCED EITHER BY TRAUMA AND SHOCK OR BY TRAUMA AND BLEEDING. THESE DATA PROVIDE STRONG SUPPORT FOR SUPERFVA AS A TARGETED APPROACH FOR THE TREATMENT OF ATC. THE OBJECTIVES FOR THIS PROJECT ARE: 1) TO PROVIDE PROOF OF CONCEPT THAT CORRECTION OF ATC BY SUPERFVA IMPROVES CLINICALLY RELEVANT OUTCOMES AFTER TRAUMA SUCH AS ORGAN DAMAGE AND SURVIVAL, AND 2) TO DEMONSTRATE THAT SUPERFVA HAS A FAVORABLE THROMBOGENICITY RISK/BENEFIT RATIO DUE TO ITS UNIQUE CHARACTERISTICS. PROOF OF CONCEPT THAT CORRECTION OF ATC BY SUPERFVA IMPROVES SURVIVAL AND ORGAN HEALTH OUTCOMES WILL HAVE AN UNPRECEDENTED SCIENTIFIC AND CLINICAL IMPACT FOR TREATMENT AND RESCUE OF TRAUMA PATIENTS WITH ATC AND PROVIDES STRONG PRECLINICAL SUPPORT FOR THE NEXT IND-ENABLING DEVELOPMENT PHASE OF SUPERFVA FOR TREATMENT OF ATC THAT WILL BE THE SUBJECT OF A PHASE 2 APPLICATION.

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PRIMARY CARE

SEC. 9007 REAP-ENERGY EFFICIENCY IMPROVEMENTS GRANTS (MAN)