ROSLYN, NY, United States
ROSLYN, NY, United States

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Zhang Y.,Feinstein Institute for Medical Research | Brenner M.,Feinstein Institute for Medical Research | Brenner M.,Therasource, Llc | Yang W.-L.,Feinstein Institute for Medical Research | And 2 more authors.
Laboratory Investigation | Year: 2015

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive system and typically requires lifelong medical care. Recombinant human MFG-E8 (rhMFG-E8) is a 364-amino acid protein, which promotes apoptotic cell clearance and reduces inflammation. This study investigates the therapeutic effect of rhMFG-E8 on two well-established mouse models of IBD. Acute mucosal injury leading to colitis was caused by exposing C57BL/6 mice to 4% dextran sodium sulfate (DSS) in the drinking water over 7 days, and BALB/c mice to a single intrarectal dose of 2.75 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Upon clinical onset of colitis (day 2 in the DSS model and day 1 in the TNBS model), mice were treated with daily subcutaneous injections of rhMFG-E8 (60 or 120 μg/kg/day) or vehicle (saline) for 6 days. Treatment with rhMFG-E8 significantly attenuated colitis in both models in a dose-dependent way. Treatment of DSS-induced colitis with rhMFG-E8 (120 μg/kg/day) decreased weight loss by 59%, the colitis severity score by 71%, and colon shrinkage by 49% when compared with vehicle. Similarly, treatment of TNBS-induced colitis with rhMFG-E8 (120 μg/kg/day) decreased weight loss by 97%, the colitis severity score by 82%, and colon shrinkage by 62% when compared with vehicle. In both models, the colons of animals receiving rhMFG-E8 showed marked reduction in neutrophil infiltration, cytokine and chemokine expression, and apoptotic cell counts. In conclusion, rhMFG-E8 ameliorates DSS-and TNBS-induced colitis, suggesting that it has the potential to become a novel therapeutic agent for IBD. © 2015 USCAP, Inc All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 540.42K | Year: 2016

PROJECT DESCRIPTION This SBIR Phase II proposal is intended to further develop human ghrelin hGhr and human growth hormone hGH as a combination therapy for elderly patients with sepsis and septic shock In the US more than one million people develop sepsis every year and nearly of septic deaths occur in patients older than years of age Currently no effective pharmacotherapy exists for the treatment of sepsis One of the reasons for sepsis clinical trial failures is that the preclinical evaluation of anti sepsis drug candidates has been conducted exclusively in young animals Rat Ghr for example ameliorates sepsis in young but not aged rats We have discovered that administration of GH upregulates the expression of the Ghr receptor and restores Ghr s responsiveness in aged animals with sepsis In our completed SBIR Phase I project co administration of hGhr and hGH hGhr hGH significantly ameliorated sepsis associated lung liver and kidney injury in septic aged animals We further demonstrated that the combination therapy nearly doubled the survival rate of septic aged rats Moreover both hGhr and hGH have been clinically tested and used for other indications with an excellent safety profile Based on our Phase I results we hypothesize that hGhr hGH can be further developed as an effective therapy for sepsis in the elderly To advance hGhr hGH therapy towards its clinical use against sepsis in the elderly we plan to determine the combination therapy s most effective dose and therapeutic window to attenuate tissue injury and improve survival We will also study hGhr hGH s combination effects on safety and pharmacokinetics PK Finally we will conduct an exploratory study in an ovine model of sepsis to evaluate hGhr hGH s effects on hemodynamic parameters and organ injury These proposed studies should provide crucial information for the future filing of an IND application to further develop hGhr hGH in clinical trials Our ultimate goal is to obtain FDA approval for the use of hGhr hGH as a safe and effective treatment for elderly patients with sepsis and septic shock PUBLIC HEALTH RELEVANCE STATEMENT Sepsis is a major cause of death in the United States but there is no effective FDA approved treatment for sepsis Attempts to treat sepsis have failed in part because new treatments are only tested in sepsis models with young animals while most patients with sepsis are at least years old We have shown that treatment with a combination of two human hormones ghrelin and growth hormone improves sepsis outcomes in aged animals We plan to further develop this combination therapy toward its future approval by the FDA as a new treatment for elderly patients with sepsis and septic shock


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.89K | Year: 2014

DESCRIPTION (provided by applicant): The ultimate goal of our proposal is to develop a novel therapeutic approach that will save lives of aged septic patients. Sepsis is the most common cause of death in the non-cardiac intensive care units (ICU). It is particularly a serious problem in the geriatric population. The elderly (e 65 years of age) accounts for 12% of the US population but 65% of sepsis cases. Nearly 80% of septic deaths occur in elderly patients. Although this problem is increasingly recognized, current treatment options for aged septic patients are very limited. Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor 1a (GHSR1a, i.e., ghrelin receptor). We have shown that administration of ghrelin inhibits inflammatoryresponses, attenuates organ injury, and reduces mortality in young septic animals. Ghrelin's beneficial effects are attributed to the activation of the vagus nerve through ghrelin receptors in the brain. We have also shown a greater production of pro


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 222.51K | Year: 2016

PROJECT DESCRIPTION The primary objective of this project is to demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor factor rhMFG E as a novel and effective therapeutic for patients with acute kidney injury AKI associated with ischemia due to low renal perfusion AKI is a major cause of prolonged hospitalization and increased mortality Ischemic AKI often results from decreased renal blood flow associated with cardiac surgery involving cardiopulmonary bypass especially coronary artery bypass graft and valve replacement Despite being a frequent life shortening and costly complication no FDA approved drugs are currently clinically available to treat ischemic AKI MFG E is a protein that promotes the clearance of inflammation promoting dying cells and decreases the influx of tissue damaging neutrophils to the injured site In the preliminary study we used recombinant mouse MFG E to treat mice with AKI induced by severe renal ischemia reperfusion Treatment with recombinant mouse MFG E significantly attenuated renal dysfunction decreased levels of proinflammatory cytokines and reduced kidney infiltration by neutrophils Therefore we hypothesize that rhMFG E can be developed as a new and effective biologic drug to treat patients with ischemic AKI Indeed administration of His tagged rhMFG E increased the day survival of mice with ischemic AKI from to Since His tagged proteins are not suited for use in humans we have started to produce a druggable human like glycosylated His tag free rhMFG E using a mammalian Chinese hamster ovary CHO cell expression system In this project we will express purify and characterize CHO expressed rhMFG E We will next determine CHO expressed rhMFG E andapos s efficacy to attenuate renal injury and improve survival after ischemic AKI and its pharmacokinetic PK profile in healthy and AKI animals Our future steps SBIR Phase II and beyond include completing preclinical and safety studies establishing ADME and safety studies determining efficacy in a second species and filing an investigational 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 biologic drug to treat patients with ischemic AKI PUBLIC HEALTH RELEVANCE STATEMENT During many common surgical procedures such as coronary artery heart valve replacement and cancer surgery the blood flow to the kidneys may drop resulting in acute kidney injury Acute kidney injury leads to a loss of kidney function longer hospital stays expensive treatments and increased death Yet there is no good treatment for patients with acute kidney injury We have shown that a protein called MFG E strongly protects experimental animals from acute kidney injury and improves their survival Therefore we propose to develop the human form of MFG E as a new and powerful way to treat surgery associated acute kidney injury


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.56M | Year: 2011

DESCRIPTION (provided by applicant): This SBIR Phase II proposal is a plan to further develop a novel therapeutic approach that will save the lives of patients with sepsis. Despite the increased understanding of the complex pathophysiology of sepsis, severe sepsis still results in significant morbidity and mortality. As such, there is an urgent unmet medical need for an effective novel therapy for septic patients. The global market potential for sepsis treatment is estimated at over 30 billion annually. Thus, successful development of a new anti-sepsis therapy will not only have a positive impact on health care, but also will have significant commercial benefits. A balanced inflammatory response is an essential element of a successful host defense after injury. However, excessive production of proinflammatory cytokines may cause further tissue injury. Macrophages/Kupffer cells play important roles in producing proinflammatory cytokines in sepsis. The nervous system reflexively regulates the inflammatory response in real time. We have demonstrated that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the gut is increased in sepsis, and that NE potentiates endotoxin-induced TNF-( upregulation via the A subtype of (2-adrenoceptors (i.e., (2A-AR) expressed on the surface of Kupffer cells. Pre-treatment with a specific (2A-AR antagonist, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL- 44408 maleate), downregulates TNF-(, attenuates tissue injury,and improves survival in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). However, it remained unknown whether the delayed administration of BRL-44408 maleate (which is more clinically relevant) reduces sepsis-induced mortality as well. Accordingly, the primary objective of our completed Phase I project was to determine the effect of delayed administration of BRL-44408 maleate on sepsis-induced inflammation, organ injury, and mortality. We have clearly shown that administration of BRL-44408 maleate at 5 h after CLP (i.e., at the early stage of sepsis) is protective in experimental animals. These results have established the technical merit and feasibility of the proposed Phase II project. We therefore continue to hypothesizethat the administration of the small molecule drug candidate BRL-44408 maleate in established sepsis attenuates tissue injury and improves survival. In this Phase II proposal, we will perform detailed toxicological evaluation and pharmacokinetic characterization, and determine the optimal protective dose(s) and time- course of BRL-44408 maleate in sepsis in the rat. In order to advance the technology to clinical trials, the efficacy of BRL-44408 maleate will be tested in a rabbit model of sepsis. These proposed studies should provide important preclinical data that will help us filing an IND application to the FDA to initiate clinical trials in order to obtain commercial utilization of BRL-44408 maleate as a safe and effective therapy for sepsis. PUBLIC HEALTH RELEVANCE: Sepsis is one of the leading causes of death in intensive care units. Over 210,000 people succumb to this overwhelming infection in the United States annually. A recent epidemiologic study estimated that more than 750,000 people develop sepsis each year at a cost of 16.7 billion nationally. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. Thus, there is an urgent unmet medical need for an effective novel therapy for patients with sepsis.


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


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: | Program: SBIR | Phase: Phase II | Award Amount: 1.23M | Year: 2010

DESCRIPTION (provided by applicant): The purpose of this SBIR Phase II proposal is to further develop a novel treatment that will be used to save the lives of patients with intestinal ischemia/reperfusion (I/R) injury. Although various modalities and substances have been studied to reduce intestinal I/R-induced mortality, none have been entirely successful. As such, the development of novel treatments to prevent or at least minimize intestinal I/R injury is of tremendous benefit to the patient. The market potential for intestinal I/R treatment as a whole is estimated at 2-5 billion per year in the US alone. We have recently demonstrated that administration of rat adrenomedullin (AM), a recently-discovered potent vasoactive peptide, in combination with human adrenomedullin binding protein-1 (AMBP-1), a novel specific binding protein of AM, immediately at the beginning of reperfusion attenuated tissue injury and inflammatory responses in a rat model of intestinal I/R induced by superior mesenteric artery occlusion (SMAO). To avoid the potential immunogenicity of rat proteins in humans, human AM was proposed in the Phase I project. The above protective effects have been confirmed using commercial human AMBP-1 in combination with human AM in the same animal model of SMAO. The dose-response study showed that the highest dosage of human AM/AMBP-1 proposed in the Phase I project achieved a better protection after intestinal I/R. However, the extremely high cost of commercial human AMBP-1 limits the further development of AM/AMBP-1. To overcome this obstacle, we have successfully isolated and purified AMBP-1 from human serum at a much lower cost. We therefore continue to hypothesize that administration of human AM/AMBP-1 attenuates organ injury and inflammation, and reduces mortality following after intestinal I/R injury. In this Phase II proposal, we will first scale up the production of human AMBP-1 and, then, perform additional efficacy studies in order to determine the optimal protective dosage of human AM/AMBP-1 in intestinal I/R in the rat. Moreover, the pharmacokinetic characterization of human AM/AMBP-1 after intestinal I/R will be assessed. To advance our technology to the clinical trials, the efficacy of human AM/AMBP-1 will be investigated in a swine model of intestinal I/R. Our ultimate goal is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with intestinal I/R injury. PUBLIC HEALTH RELEVANCE: Intestinal ischemia-reperfusion (I/R) is a common clinical problem in the settings of sepsis, hemorrhagic shock, vascular surgery and small bowel transplantation. Although various modalities and substances have been studied to reduce intestinal I/R-induced mortality, none have been entirely successful. As such, the development of novel treatments to prevent or at least minimize intestinal I/R injury is of tremendous benefit to the patient. The market potential for intestinal I/R treatment is estimated at 2-5 billion per year in the US alone. It is obvious that there is an urgent medical need for the development of an effective and novel resuscitation approach for the treatment of patients with intestinal I/R injury.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.25M | Year: 2013

Despite advances in our understanding of excessive alcohol intake-related tissue injury, high morbidity and mortality due to infections in alcohol abusers remain a prominent challenge. Milk fat globule epidermal growth factor-factor VIII (MFG-E8) is involved in the clearance of apoptotic cells. We previously discovered that acute alcohol exposure and infections down regulate MFG-E8 expression. Administration of recombinant murine MFG-E8 (rmMFG-E8) reduces apoptosis, decreases inflammatory responses, and attenuates organ damage in a rat model of acute alcohol exposure and subsequent polymicrobial infections. However, one obstacle that hampered development of MFG-E8 as a therapeutic agent for alcoholic patients with infections is the potential immunogenicity of animal proteins in humans. To overcome this, we successfully expressed and purified recombinant human MFG-E8 (rhMFG-E8), and our data indicated that rhMFG-E8 is as effective as animal MFG-E8. In our SBIR Phase I Contract, we scaled up the production of recombinant human MFG-EB (rhMFG-EB) and confirmed the beneficial effect of rhMFG-EB in a rodent model of acute alcohol exposure and sepsis. The goal of this SBIR Phase II Contract is targeted towards completing the preclinical development of rhMFG-EB as a novel therapeutic agent in reducing mortality after alcohol/sepsis. PUBLIC HEALTH RELEVANCE

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