Preclinical drug trial in mouse models of inflammation

Summary

Principal Investigator: Kanneboyina Nagaraju
Abstract: DESCRIPTION (provided by applicant): The Candidate, a veterinarian with Master's and PhD degrees in immunology, has a long-standing interest and expertise in generating and phenotyping transgenic mouse models for inflammatory diseases. A major stumbling block in moving potential therapeutic approaches for rare diseases from the laboratory bench to human clinical trials involves obtaining "pre-clinical" data in mouse models of human disease. There is currently no mouse phenotyping and drug screening facility in the USA that is capable of screening large numbers of drugs or other experimental therapeutics particularly for rare inflammatory muscle diseases. The Candidate has established a state-of-the-art murine phenotyping and drug testing facility for neuromuscular disease mouse models at the Children's National Medical Center and is currently leading international efforts to develop standard operating procedures to define preclinical endpoints for evaluating therapeutic interventions in murine models of neuromuscular disorders. This award will help establish 1) a structured training and mentoring program for junior faculty, post-doctoral fellows, graduate students, technicians, and trainees from around the country that is focused on the molecular and functional pathobiology of muscle diseases in mouse models;and 2) help the Candidate develop and extend his research and training related to evaluating the therapeutic efficacy of modern drugs in these models of rare human diseases. Glucocorticoids (GCs) have been successfully used in the treatment of many acute and chronic inflammatory diseases for several decades. The main reason that these drugs are very effective in multiple disease conditions is due to their ability to simultaneously block the inflammatory cascade at multiple stages. The major limitation of steroid prescription is that these desired anti-inflammatory effects are generally accompanied by drastic side effects such as diabetes mellitus, peptic ulcer, Cushing's syndrome, osteoporosis, skin atrophy, psychosis, glaucoma, and many others upon chronic use. Therefore there is an urgent need for the development of compounds with the anti- inflammatory potency of standard GCs but with reduced side effects. It has been proposed that beneficial effects are due to GC-glucocorticoid receptor (GR) mediated transrepressive (NF-kB inhibition) activities in cytoplasm and side effects (metabolic and hormonal) are thought to be predominantly mediated by transactivation via GC response elements in the nucleus. Thus, ligands that preferentially induce the transrepression and not transactivation function of the GR are ideal for treating chronic inflammatory conditions. Our group, in collaboration with Validus Biopharma (VBP), has identified and tested several GC analogues that efficiently block inflammation by inhibiting NF-kB activity in skeletal muscle cells. In this proposal we hypothesize that these novel non-hormonal steroids significantly reduce inflammation and improve muscle function, arthritis and asthma phenotypes without causing significant adverse effects. Aim.1. Test efficacy and toxicity VBP-3 and VBP15 in mouse model of LGMD2B using well-characterized functional, behavioral, immunological, imaging, and histological assays. Aim.2. Assess the efficacy and toxicity of VBP-3 and VBP15 in this arthritis mouse model using clinical, histological and imaging assays. Aim 3. Evaluate efficacy of VBP3 and VBP15 systematically using immunological and histological endpoints. Study Design: All aims use murine models and normal mouse strains. Relevance: These experiments could provide the basis for future human clinical trials with non-hormonal steroids, not only for dystrophies but also for arthritis, asthma and several human immune and inflammatory diseases. This program will help the Candidate to train and develop scientists interested in drug development in academic settings. These efforts in the long term will help us to develop specific drugs for inflammatory diseases. PUBLIC HEALTH RELEVANCE (provided by applicant): This proposal involves training and mentoring students, fellows, and junior investigators in mouse pathobiology as well as performing preclinical efficacy of non-hormonal steroids in a mouse model of limb girdle muscular dystrophy 22B, rheumatoid arthritis and asthma. We will use state-of-the-art comprehensive preclinical assessments and evaluations of drug efficacy and toxicity in these mouse models. This proposal will help to train a pool of talented young scientists to pursue mouse model research and accelerate development of therapies for inflammatory diseases.
Funding Period: -------------------2 - ------------------20
more information: NIH RePORT

Top Publications

  1. pmc The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands
    Kitipong Uaesoontrachoon
    Research Center for Genetic Medicine, Children s National Medical Center, Washington, DC, USA
    J Pathol 231:199-209. 2013
  2. pmc Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy
    Qing Yu
    Center for Genetic Medicine Research, Children s National Medical Center, Washington DC, United States of America
    PLoS ONE 8:e65468. 2013
  3. pmc VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice
    Jesse M Damsker
    ReveraGen BioPharma, Rockville, Maryland, United States of America
    PLoS ONE 8:e63871. 2013
  4. pmc VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid
    Erica K M Reeves
    ReveraGen BioPharma, Inc, 9700 Great Seneca Hwy Rockville, MD 20910, USA
    Bioorg Med Chem 21:2241-9. 2013
  5. pmc Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse
    Sree Rayavarapu
    Research Center for Genetic Medicine, Children s National Medical Center, 111 Michigan Ave NW, Washington, DC, USA
    Mol Cell Proteomics 12:1061-73. 2013
  6. pmc Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model
    Vanessa E Jahnke
    Center for Genetic Medicine Research, Children s National Medical Center, Washington, DC, USA
    Skelet Muscle 2:16. 2012
  7. pmc The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy
    William Coley
    Children s National Medical Center, Washington, DC, USA
    Arthritis Rheum 64:3750-9. 2012
  8. pmc IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse
    Matthew C Kostek
    Laboratory of Muscle and Translational Therapeutics, Department of Exercise Science, University of South Carolina, Columbia, SC, USA
    BMC Musculoskelet Disord 13:106. 2012
  9. pmc Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy
    Kitipong Uaesoontrachoon
    Research Center for Genetic Medicine, Children s National Medical Center, Washington, DC, USA
    Hum Mol Genet 23:3239-49. 2014

Detail Information

Publications10

  1. pmc The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands
    Kitipong Uaesoontrachoon
    Research Center for Genetic Medicine, Children s National Medical Center, Washington, DC, USA
    J Pathol 231:199-209. 2013
    ..These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR-7/8 antagonists may have therapeutic value in this disease...
  2. pmc Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy
    Qing Yu
    Center for Genetic Medicine Research, Children s National Medical Center, Washington DC, United States of America
    PLoS ONE 8:e65468. 2013
    ..One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients...
  3. pmc VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice
    Jesse M Damsker
    ReveraGen BioPharma, Rockville, Maryland, United States of America
    PLoS ONE 8:e63871. 2013
    ..These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases...
  4. pmc VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid
    Erica K M Reeves
    ReveraGen BioPharma, Inc, 9700 Great Seneca Hwy Rockville, MD 20910, USA
    Bioorg Med Chem 21:2241-9. 2013
    ..VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24-42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy...
  5. pmc Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse
    Sree Rayavarapu
    Research Center for Genetic Medicine, Children s National Medical Center, 111 Michigan Ave NW, Washington, DC, USA
    Mol Cell Proteomics 12:1061-73. 2013
    ..In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease...
  6. pmc Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model
    Vanessa E Jahnke
    Center for Genetic Medicine Research, Children s National Medical Center, Washington, DC, USA
    Skelet Muscle 2:16. 2012
    ..abstract:..
  7. pmc The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy
    William Coley
    Children s National Medical Center, Washington, DC, USA
    Arthritis Rheum 64:3750-9. 2012
    ..In particular, it has been suggested that an acquired deficiency of AMP deaminase 1 (AMPD1) may be responsible for muscle weakness in myositis...
  8. pmc IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse
    Matthew C Kostek
    Laboratory of Muscle and Translational Therapeutics, Department of Exercise Science, University of South Carolina, Columbia, SC, USA
    BMC Musculoskelet Disord 13:106. 2012
    ..The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse...
  9. pmc Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy
    Kitipong Uaesoontrachoon
    Research Center for Genetic Medicine, Children s National Medical Center, Washington, DC, USA
    Hum Mol Genet 23:3239-49. 2014
    ..In conclusion, our results indicate that naproxcinod has significant potential as a safe therapeutic option for the treatment of muscular dystrophies...