?Fibroproliferative illnesses leading to organ fibrosis and failure are responsible for approximately 45% of deaths in developed countries; whether idiopathic, triggered by environmental factors, infections, or genetics, organ fibrosis results in significant morbidity and mortality. Organ fibrosis is responsible for health care costs exceeding $10 billion/year. It is estimated that the number of deaths due to fibrosis is double the number of deaths due to cancer, and that organ fibrosis results in significant physical, emotional, and financial burdens. Specifically, lung fibrosis can be idiopathic, associated with connective tissue diseases, or triggered by environmental and occupational exposures such as radiotherapy. There are currently no effective therapies to treat existing lung fibrosis, and the only option for patients is organ transplantation. We have identified a peptide derived from endostatin, now called Endopep, which exerts anti-fibrotic effects in vitro, ex vivo, and in vivo in pre-clinical models of lung fibrosis. Endopep was effective whether administered concomitantly with the fibrotic trigger or days after the trigger, and appears to reverse fibrosis, an effect not seen wit other drugs being evaluated for these illnesses. We propose to produce recombinant Endopep by transient expression in whole plants and test the efficacy of the plant-made product in our in vitro, ex vivo, and in vivo pre-clinical models of fibrosis. We also propose to conduct pharmacokinetic, pharmacodynamic, biodistribution, and early toxicity studies in preparation for an IND application. We have assembled a unique team with the expertise to express the peptide in plants, conduct the pre-clinical testing, and complete the early PK, PD, biodistribution and toxicity studies in order to translate our findings to the clinic.
Public Health Relevance Statement: Public Health Relevance: Pulmonary fibrosis is a terminal complication of diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). We have identified a novel peptide with anti-fibrotic activity that is effective at blocking and reversing lung fibrosis We propose to manufacture the peptide in plants, test the plant-made product for efficacy in our pre-clinical models, and conduct pharmacokinetic, biodistribution, and early toxicity studies in preparation for IND application filing.
NIH Spending Category: Autoimmune Disease; Lung; Orphan Drug; Rare Diseases; Scleroderma
Project Terms: base; Biodistribution; Biological Assay; Bleomycin; Cause of Death; Cessation of life; chemical synthesis; Clinic; Clinical Trials; Collagen; Collagen Type XVIII; commercialization; Complication; Connective Tissue Diseases; connective tissue growth factor; cost; Data; Dermal; Developed Countries; Disease; Drug Kinetics; Early Diagnosis; effective therapy; efficacy testing; Emotional; Endostatins; Environmental and Occupational Exposure; Environmental Risk Factor; Extracellular Matrix; Failure (biologic function); Fibronectins; Fibrosis; Genetic; Goals; Hamman-Rich syndrome; Health Care Costs; Homeostasis; Human; Hydroxyproline; In Vitro; in vitro activity; in vivo; indium-bleomycin; Infection; Insulin-Like Growth Factor Binding Protein 3; Interstitial Collagenase; Lead; Lung; Lung Transplantation; Malignant Neoplasms; Messenger RNA; Metabolic; metabolic abnormality assessment; Metabolism; Morbidity - disease rate; Mortality Vital Statistics; Mus; novel; Organ; Organ failure; Organ Transplantation; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plants; Pre-Clinical Model; Preparation; prevent; Production; public health relevance; Pulmonary Fibrosis; Radiation therapy; Recombinants; research clinical testing; response; Skin; Stromelysin 1; synthetic peptide; Systemic Scleroderma; Tenascin; Testing; Therapeutic; Therapeutic Effect; Thick; Toxic effect; Transforming Growth Factor beta; Translating; Urokinase; Wit; Wound Healing
