Scleroderma (systemic sclerosis, SSc) is an autoimmune fibrotic disorder that affects multiple systems including the skin and visceral organs of the body. The leading cause of death in scleroderma patients is pulmonary dysfunction resulting from progressive interstitial lung fibrosis. Although immunosuppressive agents and other drugs such as nintedanib may stabilize lung function, long-term treatment is required, significant toxicity may occur, and many patients fail to respond to such therapies. Around 40% of scleroderma-associated interstitial lung disease (SSc-ILD) patients will die within 10 years of diagnosis; therefore, there is an urgent need for new therapeutic approaches that would be more effective and less toxic than current treatments. Small peptides are widely involved in multiple cellular events and play very important roles in various cell functions. Interest in peptides as potential drug candidates remains high. With advances in such fields as chemical synthesis and peptide formulation, peptide drugs - especially short synthetic and long-acting peptides - are quickly increasing in the global market. The advantages of small peptides as drugs include their high biological activity, high specificity, and low toxicity. FibroBiologics, LLC proposes to develop the novel peptide M10 as an efficacious antifibrotic therapeutic agent, with a lead indication for the treatment of patients who suffer from SSc-ILD. In Specific Aim 1, we will determine basic PK parameters, metabolism, biodistribution, and toxicity of M10 after subcutaneous administration in mice. In Specific Aim 2, we will define the efficacious dosing of M10 in two different animal models of SSc-ILD: bleomycin-induced therapeutic mouse model and FSP-driven T?R1CA mouse model. The successful completion of these two specific aims will provide important information about the feasibility of developing M10 as a novel antifibrotic therapeutic and will justify further studies focusing on gaining FDA clearance, scaling production, and a human clinical trial. Public Health Relevance Statement Project Narrative In this Phase I STTR, FibroBiologics, LLC will determine basic PK parameters, metabolism, biodistribution, and toxicity of a novel antifibrotic peptide M10 and prove its feasibility in two different animal models of SSc-ILD: bleomycin-induced therapeutic mouse model and FSP- driven T?R1CA mouse model. The impact of the proposed work on public health will be significant, as it will contribute to the development of an effective strategy for the treatment of SSc-ILD. Moreover, the M10-based therapeutics developed in our study might be effective in other pathological conditions and diseases characterized by excessive scarring and fibrosis.
Project Terms: Affect ; Amino Acids ; aminoacid ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Biological Response Modifier Therapy ; Biologic Therapy ; Biological Therapy ; biological therapeutic ; biological treatment ; biotherapeutics ; biotherapy ; Biotechnology ; Biotech ; Bleomycin ; Bleo ; Body Weight ; Bronchoalveolar Lavage Fluid ; Cause of Death ; Cell physiology ; Cell Function ; Cell Process ; Cellular Function ; Cellular Physiology ; Cellular Process ; Subcellular Process ; chemical synthesis ; Chemistry ; Cicatrix ; Scars ; Clinical Trials ; Collagen ; Connective Tissue Diseases ; Connective Tissue Disorder ; Scleroderma ; dermatosclerosis ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Fibroblasts ; Fibrosis ; Goals ; Hematology ; Histology ; Human ; Modern Man ; Immunosuppressive Agents ; Immunosuppressants ; Immunosuppressive drug ; Immunosuppressive treatment ; immune suppressive agent ; immune suppressor ; immunosuppressive substance ; immunosuppressor ; Inflammation ; Kidney ; Kidney Urinary System ; renal ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Liver ; hepatic body system ; hepatic organ system ; Lung ; Lung Respiratory System ; pulmonary ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Organ Weight ; Legal patent ; Patents ; Patients ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Play ; Production ; Proteins ; Public Health ; Pulmonary Fibrosis ; lung fibrosis ; Quantitative Evaluations ; Role ; social role ; Systemic Scleroderma ; Systemic Sclerosis ; progressive systemic sclerosis ; Specificity ; Spleen ; Spleen Reticuloendothelial System ; Tissues ; Body Tissues ; Woman ; Work ; cytokine ; Extracellular Matrix Proteins ; base ; Organ ; Clinical ; Phase ; Biological ; Interstitial Lung Diseases ; Receptor Protein-Tyrosine Kinases ; PTK Receptors ; Receptor Tyrosine Kinase Gene ; Transmembrane Receptor Protein Tyrosine Kinase ; Tyrosine Kinase Linked Receptors ; Tyrosine Kinase Receptors ; Serum ; Blood Serum ; pulmonary function ; lung function ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; ALK-5 protein ; ALK-5 receptor ; ALK5 ; Activin A Receptor Type II-Like Kinase 53kDa ; Activin Receptor-Like Kinase 5 ; SKR4 ; Serine/Threonine-Protein Kinase Receptor R4 ; TGFBR-1 ; Transforming Growth Factor Beta Receptor I ; Transforming Growth Factor Beta Receptor Type I ; TGF-beta type I receptor ; Therapeutic ; Therapeutic Agents ; Deposit ; Deposition ; Area Under Curve ; milligram ; Complex ; Event ; Visceral ; subdermal ; subcutaneous ; System ; interest ; interstitial ; Receptor Protein ; receptor ; success ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; novel ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Lung Parenchyma ; Lung Tissue ; Structure of parenchyma of lung ; Modeling ; Property ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Skin ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; HGF Receptor ; HGFR ; Hepatocyte Growth Factor Receptor ; MET Protooncogene ; MET gene ; Address ; Dose ; Preventive ; Data ; Preclinical Models ; Pre-Clinical Model ; Small Business Technology Transfer Research ; STTR ; Pathologic ; Process ; Development ; developmental ; Minority ; Biodistribution ; C-terminal ; mouse model ; murine model ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; treatment strategy ; preclinical evaluation ; pre-clinical evaluation ; good laboratory practice ; drug candidate ; immune activation ; Immune Cell Activation ; skin fibrosis ; cutaneous fibrosis ; dermal fibrosis ; fibrotic skin ; Formulation ; peptide drug ; therapeutic peptide ; preclinical development ; pre-clinical development ; secondary endpoint ; secondary end point ; primary endpoint ; primary end point ; vascular injury ; injury to the vasculature ; Autoimmune ; tocilizumab ; Actemra ;
