A Novel Thioredoxin Mimetic Prodrug for Prevention of Bronchopulmonary Dysplasia

Summary

Principal Investigator: Prakash Jagtap
Abstract: DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a novel pharmaceutical therapy for prematurity that targets a developmental deficiency in thioredoxin (Trx), a protein that serves as a central regulator of cellular reductant status. Trx is expressed t levels in the fetal lung too low to adequately counter the redox stress of extrauterine life, and i thus relatively deficient in extreme prematurity. The low level of Trx in alveoli is thought to pla a major role in the susceptibility of very low birthweight (VLBW) premature infants to neonatal respiratory distress syndrome (RDS). Our current understanding of RDS and its evolution into bronchopulmonary dysplasia (BPD) is consistent with a mechanism of injury produced by an excess of superoxide within the lung parenchyma. Compounding this increase in superoxide production is the developmental deficiency of anti-oxidant proteins, such as superoxide dismutase and Trx, that are present in insufficient quantity at an early gestational age. Our innovation is based upon the administration of a novel agent, R-908, a prodrug of a Trx mimetic (R-901) that substitutes for the deficient Trx protein and restores intracellular redox status. R-901 is a thiol-rich tripeptide closely analogous to the native conserved Trx motif and exhibits extraordinary potency: R- 901 is 450-fold more potent than N-acetyl cysteine in the protection of cultured cells from oxidant stress. In a murine ovalbumin model of pulmonary inflammation model, R-901 reduced histologic injury, diminished neutrophil infiltration, attenuated tissue oxidation, blocked pro-inflammatory cytokine expression and nuclear translocation of NF-?B, diminished the degradation of the anti-inflammatory cytoplasmic protein I?B[unreadable], and restored the balance of reduced and oxidized forms of glutathione. In a murine LD60 model of redox stress, induced by acute Cl2 inhalation, post-insult administration of R-901 eliminated all mortality. To overcome shelf instability of the free thiol groups of R-901, we have invented a stable dithioester prodrug (R-908) that releases R-901 in vivo. R-908 will now undergo evaluation in a clinically-relevant rat pup model of BPD. Aim #1: Define the pharmacokinetics (PK) of R-908 in newborn rats. We will define the plasma and tissue PK profile of R-908, and its metabolite R-901, in 2-day old rat pups. Aim #2: Establish that R-908 attenuates changes of pulmonary vascular and alveolar structure in a hyperoxic model of BPD in neonatal rats;2-day old rat pups will be subjected to hyperoxia for 10 days. R-908 will be administered over a broad dose range for 3 weeks, a period characterized in this model system by progressive lung fibrosis, pulmonary arterial hypertension (PAH), and hypoalveolarization. Lung tissue taken at necropsy will be analyzed for pulmonary vascular structure and growth, alveolarization, lipid peroxidation (malondialdehyde), reduced and oxidized glutathione (GSH, GSSG), peroxynitrite formation (3-nitrotyrosine), poly(ADP-ribose) formation, fibrosis (Mason Trichrome staining for collagen), R-908 and R-901 levels, and pro-inflammatory gene expression. The heart will undergo morphometric analysis for evidence of PAH (as shown by right ventricular (RV) hypertrophy).
Funding Period: 2013-08-05 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. A Bifunctional Katp Channel Activator and Redox Mimetic for BPD
    Kanneganti Murthy; Fiscal Year: 2013
    ....
  2. PARP Inhibitor and Redox Catalyst for Ventilatory Trauma
    Prakash Jagtap; Fiscal Year: 2013
    ..Lung concentrations of R-503 will be correlated with outcome measures, so as to construct a PD profile. ..
  3. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
    ..Thus, the DEARC will serve as a nexus of alcohol research in Central New York and as a beacon for national activities. ..
  4. Multifunctional therapeutics for treatment of acute chlorine inhalational injury
    GARRY JOHN SOUTHAN; Fiscal Year: 2013
    ..Demonstration of potent resuscitation and safety in the pre-clinical setting will provide the foundation for development of a clinical therapeutic for CILI. ..
  5. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  6. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  7. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  8. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  9. Role of hepatic and pulmonary P4501A enzymes in neonatal hyperoxic tissue injury
    XANTHI IOANNA COUROUCLI; Fiscal Year: 2013
    ....
  10. Trial of Late SURFactant (TOLSURF) to Prevent BPD - Clinical Coord Ctr
    ROBERTA ANDERSON BALLARD; Fiscal Year: 2013
    ..This research has potential to decrease chronic infant lung disease and asthma, important areas of public health, reduce cost of care, and improve long-term outcome for premature infants. ..
  11. Bifunctional Redox Catalyst &Organic Nitrate for Limb Reperfusion
    ANDREW LURIE SALZMAN; Fiscal Year: 2013
    ..IV dose range-finding and 2 week repeat-dose toxicology studies in rats and dogs, with associated toxicokinetic determinations. ..
  12. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  13. Fundamental Mechanobiology of Tumor Progression
    JAN T LIPHARDT; Fiscal Year: 2013
    ..We have also recruited clinical investigators from 2 outside institutions to compliment existing expertise and to extend the translational scope of our projects. ..
  14. Molecular mechanisms of hypoxia tolerance and susceptibility
    Gabriel G Haddad; Fiscal Year: 2013
    ..abstract_text> ..
  15. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  16. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  17. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  18. Azithromycin to prevent BPD in ureaplasma-infected preterms.
    Ken B Waites; Fiscal Year: 2013
    ....
  19. Radiocontrast Nephropathy: Redox Degradation Catalyst and Nitric Oxide Donor
    ZSUZSANNA KINGA ZSENGELLER; Fiscal Year: 2013
    ..The proposed studies will provide a rational foundation for advanced commercial development of R-100, with the intent that this product will serve as first-line prophylaxis in high-risk diabeic patients undergoing CM injection. ..
  20. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  21. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  22. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  23. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  24. Hybrid Katp Channel Opener and Redox Catalyst for Lung Transplantation
    Prakash Jagtap; Fiscal Year: 2013
    ..R-801 therapy is expected to translate into decreased primary graft dysfunction and mortality after lung transplant. ..
  25. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  26. FGF Signaling in Lung Maturation and Response to Injury
    Xin Sun; Fiscal Year: 2013
    ....
  27. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..