GALVESTON, TX, United States
GALVESTON, TX, United States

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Kantara C.,University of Texas Medical Branch | Moya S.M.,University of Texas Medical Branch | Houchen C.W.,The University of Oklahoma Health Sciences Center | Umar S.,University of Kansas Medical Center | And 4 more authors.
Laboratory Investigation | Year: 2015

In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin) 24 h after lethal radiation exposure (9 Gy, LD 100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post exposure prevents the disintegration of GI crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also upregulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24 h post exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment. © 2015 USCAP, Inc All rights reserved.


Schein C.H.,University of Texas Medical Branch | Chen D.,University of Texas Medical Branch | Ma L.,University of Houston | Kanalas J.J.,Mission Pharmacal Company | And 6 more authors.
Toxins | Year: 2012

Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Olszewska-Pazdrak B.,University of Texas Medical Branch | Olszewska-Pazdrak B.,Chrysalis Biotherapeutics, Inc. | Carney D.H.,University of Texas Medical Branch | Carney D.H.,Chrysalis Biotherapeutics, Inc.
Journal of Vascular Research | Year: 2013

Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24 h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue. Copyright © 2013 S. Karger AG, Basel.


PubMed | University of Texas Medical Branch and Chrysalis Biotherapeutics, Inc.
Type: | Journal: The AAPS journal | Year: 2017

TP508 is a synthetically derived tissue repair peptide that has previously demonstrated safety and potential efficacy in phase I/II clinical trials for the treatment of diabetic foot ulcers. Recent studies show that a single injection of TP508 administered 24h after irradiation significantly increases survival and delays mortality in murine models of acute radiation mortality. Thus, TP508 is being developed as a potential nuclear countermeasure. Because of the short plasma half-life of TP508, we hypothesize that increasing the peptide bioavailability would increase TP508 efficacy or reduce the dosage required for therapeutic effects. We, therefore, evaluated the covalent attachment of various sizes of polyethylene glycol to TP508 at either its N-terminus or at an internal cysteine. A size-dependent increase in TP508 plasma half-life due to PEGylation was observed in blood samples from male CD-1 mice using fluorescently labeled TP508 and PEGylated TP508 derivatives. Biological activity of PEGylated TP508 derivatives was evaluated using a combination of biologically relevant assays for wound closure, angiogenesis, and DNA repair. PEG5k-TP508 enhanced wound closure after irradiation and enhanced angiogenic sprouting in murine aortic ring segments relative to equimolar dosages of TP508 without enhancing circulating half-life. PEG30k-TP508 extended the plasma half-life by approximately 19-fold while also showing enhanced biological activity. Intermediate-sized PEGylated TP508 derivatives had enhanced plasma half-life but were not active in vivo. Thus, increased half-life does not necessarily correlate with increased biological activity. Nevertheless, these results identify two candidates, PEG5k-TP508 and PEG30k-TP508, for potential development as second-generation TP508 injectable drugs.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2013

Not Available


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.79M | Year: 2012

DESCRIPTION (provided by applicant): With recent radiation release from reactors in Japan and increasing probability of nuclear detonation somewhere in the world, there is a critical need for development of effective medicinal counter-measures that can bedelivered after exposure to prevent radiation-induced mortality. Adding to this need, mortality increases significantly when radiation is combined with injury (RCI). Agents to mitigate effects of radiation and RCI must therefore be developed and stockpiledfor emergency use. We proposed that TP508 (rousalatide acetate), a novel peptide drug currently in clinical trials for healing diabetic foot ulcers and fractures, may prevent RCI-induced mortality based on its acceleration of wound healing and its uniquebeneficial effects on vascular endothelial cells. Phase 1 studies demonstrated that TP508 applied topically to wounds or delivered by post-exposure injection, restored normal wound healing in irradiated animals, prevented radiation-induced up-regulation ofIL-6, and mitigated RCI-induced mortality. Post-exposure TP508 injection also delayed mortality and the onset of bacteremia following a lethal dose of radiation. Phase 2 will focus on optimization of TP508 formulations for topical and systemic delivery and refinement of these formulations to increase their stability and potential for use following a nuclear disaster. Specifc Aims include comparisons and optimization of formulations, testing stabilized peptides, and selecting best modes of delivery by measuring mitigation of mortality, protection of endothelial function and restoration of wound healing. Following a meeting with the FDA, additional GLP safety, efficacy and final formulation stability studies will be outsourced to meet specific FDA requirements for TP508 approval under the Animal Rule exemption. Upon completion of Phase 2, TP508 product(s) should be ready for pivotal Animal Rule efficacy trials and accelerated approval for emergency stockpiling to mitigate effects of nuclear radiation and RCI. PUBLIC HEALTH RELEVANCE: Following a nuclear detonation the combination of radiation and traumatic injury is expected to be much more deadly that radiation alone. We have demonstrated that TP508, a novel peptide drug in human clinical trials,mitigates effects of whole body radiation and radiation combined with injury on mortality, wound healing, and dysfunction of multiple organ systems. In Phase 2, we will optimize TP508 formulations for topical and systemic delivery and complete FDA requirements to allow TP508 to begin pivotal trials to reduce mortality from nuclear radiation exposure.


Chrysalis Biotherapeutics, Inc. | Entity website

ABOUT CHRYSALIS BIOTHERAPEUTICS ChrysalisBioTherapeutics, Inc.is a privately held biopharmaceutical company developing regenerative drugs that mimic the bodys natural signals to activate and protect endothelial progenitor cells and stem cells located within tissues to repair and regenerate tissues damaged by injury, disease, and radiation exposure ...


Chrysalis Biotherapeutics, Inc. | Entity website

The Chrysalin Solution to PreventRadiation Therapy-Induced Tissue Damage Prescriptive Use To Prevent Radiotherapy Damage To Normal Tissue and Allow More Effective Cancer Therapy Almost 70% of all patients with cancer receive radiotherapy alone or in combination with surgery or chemotherapy. The amount of radiation that can be used to control tumor growth, however, is limited by normal tissue damage ...


Chrysalis Biotherapeutics, Inc. | Entity website

THE CHRYSALIN BRAND THROMBIN PEPTIDE (TP508) TECHNOLOGY Tissue repair and regeneration is a complex natural process that involves multiple types of cells and signaling molecules needed to restore function in damaged tissues and organs. In normal undamaged tissues these signals are shut off or used only for replacement of aging cells ...


Chrysalis Biotherapeutics, Inc. | Entity website

MANAGEMENT TEAM Darrell H. Carney, PhD, President and CEO, has a proven record as a successful academic scientist and over 15 years of experience in biopharmaceutical corporate management ...

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