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ROSLYN, NY, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 399.85K | Year: 2009

DESCRIPTION (provided by applicant): Liver injury induced by hepatic ischemia and reperfusion (I/R) is a major cause of liver failure after severe trauma, thermal injury, hemorrhagic and septic shock, liver resection, or liver transplantation. Hepatic I/R contributes significantly to multiple organ failure and mortality. Although various modalities and substances have been studied to reduce hepatic I/R-induced mortality, none have been entirely successful. Thus, the development of novel treatments to prevent or at least minimize hepatic I/R injury is of tremendous benefit to the patient. The market potential for hepatic I/R treatment is estimated at gt 10 billion per year in the US alone. We have recently demonstrated that administration of human adrenomedullin (AM, a recently-discovered potent vasoactive peptide) in combination with human AM binding protein-1 (AMBP-1, a novel specific binding protein for AM) immediately at the onset of reperfusion, downregulated pro-inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. However, it remains unknown whether delayed administration of human AM/AMBP-1 (which is more clinically relevant) is also equally protective after hepatic I/R injury with or without pre-existing liver diseases such as hepatic injury induced by bile duct ligation (BDL). Another obstacle hampering the development of human AM/AMBP-1 as a novel therapeutic agent for hepatic I/R is the extremely high cost of commercial human AMBP-1. To overcome this, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore hypothesize that delayed administration of human AM/AMBP-1 attenuates hepatic injury and inflammation, and reduces hepatic I/R-induced mortality even under pre- existing liver diseases. The primary aim of this project is targeted toward demonstrating the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic approach to reduce mortality after hepatic I/R. The optimal dosage(s) of human AM/AMBP-1 (delayed treatment) will be determined by assessing 1) the dose-response effect of human AM/AMBP-1 on tissue injury and inflammatory responses after hepatic I/R; 2) the time-course of human AM/AMBP-1's beneficial effects; and 3) the effect of human AM/AMBP-1 on mortality induced by hepatic I/R with or without BDL. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with hepatic I/R injury associated with pre-existing liver conditions. PUBLIC HEALTH RELEVANCE: Recent advances in surgical techniques and pharmacological interventions have moderately improved the outcome of trauma surgery, liver resection, liver transplantation, and shock. However, liver failure due to ischemia-reperfusion (I/R) injury continues to be a major complication in the clinical arena. Hepatic I/R with or without pre-existing liver diseases contributes significantly to multiple organ failure and death of such patients. It is obvious that there is an urgent medical need for the development of novel treatments to prevent or at least minimize hepatic I/R injury.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.60M | Year: 2009

DESCRIPTION (provided by applicant): This SBIR Phase I/Phase II Fast-Track proposal is intended to develop a novel therapy for patients with sepsis and septic shock. Septic shock is the leading cause of death in non-cardiac intensive care units. Despite advances in the management of trauma victims, the incidence of sepsis and septic shock has increased significantly. More than 750,000 patients develop sepsis and septic shock each year with an overall mortality rate of 28.6% in the US alone. The global market potential for sepsis treatment is estimated at over 30 billion annually. Thus, successful development of a novel and effective anti-sepsis therapy will not only have a positive impact on health care, but will also have significant commercial benefits. Although apoptosis plays an important role in the pathobiology of sepsis, the clearance of apoptotic cells has largely been ignored. Recent evidence shows that the opsonizing protein milk fat globule epidermal growth factor-factor VIII (MFG-E8) is involved in apoptotic cell clearance. We have discovered that downregulation of MFG-E8 is responsible for the reduced apoptotic cell clearance in sepsis. Early administration of rat MFG-E8-containing exosomes or recombinant murine MFG-E8 (rmMFG- E8) increases phagocytosis of apoptotic cells, reduces proinflammatory cytokines, and improves survival in a rodent model of septic shock. However, one obstacle hampering the development of MFG-E8 as a therapeutic agent for septic patients is the potential immunogenicity of animal proteins in humans. To overcome this, we have successfully expressed recombinant human MFG-E8 (rhMFG-E8). Our data strongly suggest that rhMFG-E8 is as effective as animal MFG-E8. We therefore hypothesize that administration of rhMFG-E8, even late after the onset of sepsis, improves cardiovascular function, attenuates tissue injury and inflammation, and reduces mortality. The primary goal of this SBIR Fast-Track project is targeted toward completing the preclinical development of rhMFG-E8 as a novel therapeutic agent in reducing mortality in septic shock. In the Phase I Segment, we will 1) scale up the production of rhMFG- E8; and 2) further confirm the beneficial effect of rhMFG-E8 in a rodent model of septic shock. These readily achievable milestones should provide useful feasibility information that will allow us to conduct the proposed Phase II experiments. In the Phase II Segment, we will 3) determine the dose-response effect and time-course (delayed administration) of rhMFG-E8 on apoptosis, cardiovascular responses, tissue injury, inflammation, and survival in a rodent model of septic shock; 4) assess the toxicity and pharmacokinetic properties of rhMFG-E8 in normal and septic animals; and 5) determine the efficacy of rhMFG-E8 in a swine model of septic shock. These proposed studies should provide useful preclinical information that will allow us to file an IND application to the FDA for initiating clinical trials in order to obtain commercial utilization of rhMFG-E8 as a safe and effective therapy for patients with sepsis and septic shock.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 595.65K | Year: 2011

DESCRIPTION (provided by applicant): This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic approach that can save lives of people with radiation injury. Acute radiation injury may occur in various incidents as well as the terrorist radiation exposure scenario. Acute radiation syndrome develops after whole-body or a partial-body irradiation with a high dose of radiation. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific treatment approaches to acute radiation injury. As such, there is an urgent unmet medical need for an effective novel mitigator for patients with acute radiation injury. Ghrelin, a gastrointestinal peptide, was first identified as an endogenous ligand for the growth hormone secretagogue receptor type 1a (i.e., ghrelin receptor). Ghrelin was originally reported to induce growth hormone release through stimulation of ghrelin receptors in the central nervous system. A large body of evidence has indicated other physiological properties of ghrelin mediated by the central and peripheral ghrelin receptors. Although human ghrelin has been shown to be beneficial in certain disease conditions, it remains unknown whether this peptide can mitigate acute radiation syndrome. To study this, adult male rats were exposed to 10-Gy total body irradiation (TBI). Our preliminary data have shown that administration of human ghrelin 6 h after TBI (i.e., very early treatment) reduced mortality. However, it remains unknown whether delayed administration of human ghrelin (which is more clinically relevant) reduces TBI-induced mortality as well. We, therefore, hypothesize that delayed administration of human ghrelin after TBI attenuates tissue injury and improves survival. The primary objective of this SBIR Phase I project is targeted towards demonstrating the feasibility of the development and commercialization of human ghrelin as an effective mitigator (24 h post-radiation or later) in reducing the massive mortality after acute radiation exposure scenario. The optimal dosage(s) of human ghrelin (delayed treatment) will be determined by assessing 1) the dose-response effect of ghrelin tissue injury after TBI; 2) the dose-response effect and time-course of human ghrelin on TBI-induced mortality; and 3) the pharmacokinetics of human ghrelin in healthy and irradiated animals. Our ultimate goal (SBIR Phase II andbeyond) is to obtain commercial utilization of human ghrelin as a safe and effective mitigator for people with acute radiation injury. PUBLIC HEALTH RELEVANCE: In the wake of the September 11, 2001 terrorist attacks, the misuse of ionizing radiationor nuclear devices as weapons of terrorism has been recognized as a major public health threat. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific therapeutic approaches to radiation injury. Thus, there is an urgent unmet medical need for a novel and effective mitigator for people with acute radiation injury.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.95K | Year: 2016

DESCRIPTION provided by applicant The primary objective of this project is to further demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor factor rhMFG E as a novel and effective adjuvant therapy for the resuscitation of patients with hemorrhagic shock Hemorrhagic shock is a major cause of mortality worldwide In the United States traumatic injury is the main cause of death in individuals younger than years of age and hemorrhagic shock accounts for one third of trauma related deaths Even when treated with the standard of care and in a hospital setting of patients with hemorrhagic shock die within hours Therefore there is an unmet and critical need for a novel and effective adjuvant therapy capable of improving the success rate of the existing volume and vasoactive agents for hemorrhage resuscitation MFG E is a protein that promotes the clearance of apoptotic dying cells and inhibits the production of pro inflammatory cytokines In preliminary studies we treated hemorrhaged animals with rhMFG E and observed significant decreases in circulating pro inflammatory cytokines neutrophil infiltration to the lungs and apoptosis Treatment with rhMFG E also nearly doubled the survival rate from to Therefore we hypothesize that rhMFG E can be further developed as a new and effective adjuvant therapy for hemorrhagic shock To advance the drug development we will produce a new non His tagged rhMFG E and analyze its biological activity homogeneity and folding status We will then determine the dose dependent effects of rhMFG E on reducing organ injury hemodynamic instability pro inflammatory cytokines and histological damage caused by hemorrhagic shock Its therapeutic window to improve survival after hemorrhagic shock will be investigated Finally we will determine its safety pharmacology and pharmacokinetic profile in healthy and hemorrhaged animals Our future steps SBIR Phase II and beyond will include completing preclinical studies such as ADME studies and efficacy studies in a non rodent species as well as comparing with the standard of care We will then file an investigative new drug IND application with the FDA to initiate clinical trials Our ultimate goal is to obtain commercial utilization of rhMFG E as a safe and effective adjuvant drug for the resuscitation of patients with hemorrhagic shock PUBLIC HEALTH RELEVANCE Severe bleeding is a major cause of death worldwide In the United States trauma is the single largest cause of death in people younger than years of age Severe bleeding causes a third of trauma related deaths mostly within the first few hours after trauma Therefore a better treatment for severe bleeding is badly needed We have shown that a protein called rhMFG E strongly protected animals with severe bleeding and improved their survival from to Therefore we propose to further develop rhMFG E as a new and powerful way to treat severe bleeding


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 982.47K | Year: 2016

DESCRIPTION provided by applicant This SBIR Phase II proposal is intended to further develop human ghrelin as a radiation medical countermeasure MCM to be approved by the FDA in the future The risks of nuclear terrorism and nuclear power plant leaks still remain high both of which can cause acute radiation injury on a large scale Currently there are limited drugs available to treat acute radiation syndrome ARS Human ghrelin is a amino acid peptide hormone with broad effects on various body systems including the endocrine gastrointestinal GI cardiovascular and immune systems In our completed SBIR Phase I project we have exposed rats and mice to total body irradiation TBI and demonstrated that subcutaneous administration of human ghrelin for days starting at h post TBI significantly increased their survival rates and reduced their body weight loss We further demonstrated in the rat that treatment with human ghrelin improved intestinal integrity and reduced gut apoptosis and permeability Human ghrelin can be synthesized in large quantity for mass emergency needs Moreover human ghrelin has been tested in several clinical trials for other disease indications with an excellent safety profile Based on our positive Phase I results we hypothesize that human ghrelin can be developed as an effective post exposure mitigator for acute radiation injury In this proposal we will use the mouse model of radiation injury to identiy the dose modification factor DMF of human ghrelin to treat GI ARS and hematopoietic ARS H ARS We will also examine human ghrelinandapos s effect to attenuate hematopoietic and GI damages In addition we will conduct an exploratory study in non human primates NHP to evaluate the effect of human ghrelin treatment on the GI and hematology response to radiation exposure These proposed studies should provide crucial information on the efficacy of human ghrelin as a novel radiation MCM primarily targeting GI ARS Our ultimate goal is to obtain the FDA approval to use human ghrelin as a safe and effective treatment for people with acute radiation injury after a radiation emergency PUBLIC HEALTH RELEVANCE Radioactive exposure related to disasters accidents terrorism or war can cause radiation injury in a vast scale The gastrointestinal acute radiation syndrome is a particularly deadly form of acute radiation injury for which there is no FDA approved treatment We have shown that human ghrelin a peptide hormone improves gut injury caused by radiation and will further develop human ghrelin towards its future approval by the FDA and procurement by the US Strategic National Stockpile program

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