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Principal Investigator: Craig Lewis Duvall
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2022
Award: $204,011
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary / Abstract
Osteoarthritis (OA) is a chronic degenerative disease that affects joints and their surrounding tissues. OA can
occur spontaneously with aging or be secondary to injury in the case of post-traumatic osteoarthritis (PTOA).
OA/PTOA causes significant morbidity and loss of quality of life, resulting in an estimated financial burden in
the U.S. of over $44 billion annually. Non-steroidal anti-inflammatory drugs are typically the first line of
treatment to deal with pain but do not slow cartilage deterioration and can cause gastrointestinal problems. The
Osteoarthritis Research Society International recommends corticosteroids for temporary pain relief, but
steroids also do not target the underlying cause of disease and may even worsen cartilage thinning. These
shortcomings leave an unmet need for disease-modifying OA/PTOA drugs (DMOADs) that block or reduce
disease progression. In OA/PTOA, synoviocytes and chondrocytes produce inflammatory cytokines and
matrix metalloproteinases (MMPs) that drive the joint degenerative process. Small molecule MMP inhibitors
have been tested clinically for cancer but failed largely due to systemic toxicities caused by the lack of MMP
selectivity. RNA interference is a promising strategy for creation of target selective therapeutics against
difficult to drug molecular targets. This project is focused on development and PTOA therapeutic testing of
siRNA therapeutics that can selectively inhibit specific collagenases, either alone or in combination. The
proposed approach builds from our recent work developing siRNA molecules end-modified through a PEG
linker with a diacyl lipid (siRNA-L2), which spontaneously forms a molecular complex with albumin (alb/
siRNA-L2) in situ following intravenous injection. This albumin “hitchhiking” siRNA-L2 enhances siRNA PK, is
very safe, and increases level and homogeneity of delivery, particularly to tissues characterized by
inflammation and vascular leakiness. The overall goal of this proposal is to implement siRNA-L2 to
systemically treat and block progression of PTOA. This project will assess siRNA-L2 therapeutic index in a
PTOA mouse model and then test the disease efficacy of targeting single versus multiple proteases in a guinea
pig PTOA model.
Terms: <Adrenal Cortex Hormones><Affect><After Care><After-Treatment><Aftercare><Age-Months><Aging><Albumins><Amyloidosis><Animal Model><Animal Models and Related Studies><Animals><Anterior Cruciate Ligament><Antibodies><Assay><Binding><Bioassay><Bioavailability><Biologic Assays><Biologic Availability><Biological Assay><Biological Availability><Biology><Blood Plasma><Blood Serum><Blood Vessels><Body Tissues><Body Weight decreased><Cancers><Cartilage><Cartilaginous Tissue><Cavia><Chemicals><Chondrocytes><Chronic><Clinical><Collagen><Collagen Peptidase><Collagen Type II><Collagen-Degrading Enzyme><Complex><Corticoids><Corticosteroids><Degenerative Arthritis><Degenerative Disorder><Degenerative polyarthritis><Deterioration><Development><Disease><Disease Progression><Disorder><Dose><Drug Kinetics><Drug Targeting><Drugs><Esteroproteases><Extremities><Financial Hardship><Formulation><Fruit><Gene Expression><Gene Inactivation><Gene Silencing><Genetic Medicine><Goals><Guinea Pigs><Guinea Pigs Mammals><HPLC><Health Care Systems><Healthcare Systems><Hepatotoxic effect><Hepatotoxicity><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Histologic><Histologically><Human><In Situ><Inflammation><Inflammatory><Injury><International><Interstitial Collagenase><Intra-Articular Injections><Intraarticular Injections><Intravenous><Joint Diseases><Joints><Knee><Label><Leanness><Limb structure><Limbs><Lipids><Liver><Liver Toxicity><MMP Inhibitor><MMP-1><MMP-13><MMP-13 gene product><MMP-1Fibroblast Collagenase><MMP1><MMP13 gene product><MMPs><Malignant Neoplasms><Malignant Tumor><Matrix Metalloproteinase Inhibitor><Matrix Metalloproteinase-1><Matrix Metalloproteinases><Measures><Mechanics><Medication><Metabolic><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><NSAIDs><Nephrotoxic><Non Steroidal Antiinflammatory Agents><Non-Steroidal Anti-Inflammatory Agents><Non-Trunk><Nonsteroidal Anti-Inflammatory Agents><Nonsteroidal Antiinflammatory Agents><Nonsteroidal Antiinflammatory Drug><Organ><Osteoarthritis><Osteoarthrosis><Outcome><Pain><Painful><Palliative Care><Palliative Therapy><Palliative Treatment><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phenotype><Physiologic Availability><Plasma><Plasma Serum><Polyneuropathy><Porphyrias><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><QOL><Quality of life><Quelling><RNA Interference><RNA Silencing><RNAi><Renal clearance function><Research><Reticuloendothelial System, Serum, Plasma><Saline><Saline Solution><Secondary to><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Severity of illness><Short interfering RNA><Small Interfering RNA><Societies><Steroid Compound><Steroids><Stomach><Structural Protein><Synovia><Synovial Fluid><Testing><Therapeutic><Therapeutic Index><Thinness><Time><Tissues><Toxic effect><Toxic effect on liver cells><Toxicities><Weight Loss><Weight Reduction><Work><acute toxicity><amyloid disease><analog><arthropathic><arthropathies><arthropathy><base><behavior test><behavioral test><body weight loss><cartilage degeneration><cartilage degradation><clinical care><clinical relevance><clinical significance><clinically relevant><clinically significant><cohort><collagenase><collagenase 1><collagenase 3><comfort care><cytokine><degenerative condition><degenerative disease><degenerative joint disease><design><designing><developmental><dietary fruit><disease severity><drug/agent><financial burden><financial distress><financial strain><financial stress><fluorophore><gastric><gastrointestinal><guinea pig model><hepatic body system><hepatic organ system><hepatic toxicity><hepatoxicity><hypertrophic arthritis><improved><injuries><innovate><innovation><innovative><insight><intra-vital imaging><intravenous injection><intravital imaging><joint disorder><kidney toxicity><lipid based nanoparticle><lipid nanoparticle><malignancy><matrix metalloproteinase-13><mechanical><model of animal><model organism><molecular drug target><molecular pharmacotherapy target><mouse model><murine model><nano formulation><nanoformulation><neoplasm/cancer><nephrotoxicity><non-steroidal anti-inflammatory drugs><non-steroidal antiinflammatory drugs><nonsteroidal anti-inflammatory drugs><novel><osteoarthritic><pain relief><post treatment><relieve pain><renal clearance><screening><siRNA><siRNA therapy><siRNA-based therapeutic><side effect><small molecule><systemic toxicity><therapeutic evaluation><therapeutic siRNA><therapeutic target><therapeutic testing><transcriptional silencing><vascular><wt-loss>