Document text
Principal Investigator: Craig Lewis Duvall
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $595,117
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY/ABSTRACT
RNA interference (RNAi) using short interfering RNA (siRNA) is a promising strategy to block disease-
causing targets that are difficult to selectively and/or potently block with conventional small molecule drugs. Five
siRNA drugs are now in clinical use, all gaining FDA approval since 2018. The first siRNA drug was a lipid
nanoparticle, but subsequent drugs are “carrier-free” molecular conjugates enabled by chemical modifications
to the RNA that provide nuclease stability. Carrier-free technologies are of great interest due to manufacturing
simplicity and reduced risk of carrier (cationic polymer or lipid) associated side effects and toxicities.
siRNAs can be readily designed and optimized for hitting any gene in the body and, therefore, have
tremendous therapeutic potential. However, all siRNA drugs currently approved by the FDA aim to silence gene
expression in the liver, and no new siRNA drugs have been approved for treatment of diseases localized to or
emanating from other sites in the body.
We are optimizing siRNA conjugates for treatment of osteoarthritis (OA), a degenerative joint disease
that is a leading cause of physical disability in the United States. Current OA treatments, such as steroids, reduce
pain but can cause side effects and do not halt or slow progression of the disease. siRNA therapeutics offer the
option to block the genetic underpinnings of the disease and have the potential to yield the first disease modifying
osteoarthritis drugs (DMOADs).
The proposed project aims build 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. We have shown this albumin “hitchhiking” siRNA-L2 to be
safe and to have a high level of accumulation and on-target gene silencing activity in injured joints.
Cells residing in OA-afflicted joints produce inflammatory cytokines and matrix metalloproteinases
(MMPs) that initiate and propagate the joint degenerative process. The overall goal of this proposal is to
implement siRNA-L2 to systemically treat and block progression of PTOA and to build from promising data
showing that silencing of MMP13 has therapeutic benefit in post-traumatic OA. Specifically, this project will (1)
elucidate the mechanism of action of siRNA-L2 against MMP13 in OA, (2) test new chemical modifications for
improving joint retention and activity of siRNA-L2, (3) test for efficacy of siRNA-L2 targeting MMP13 in a larger
(non-rodent) animal model, and (4) establish the platform nature of siRNA-L2 against other gene targets
associated with pathogenesis of OA.
The investigative team for this interdisciplinary project spans RNA chemistry/therapeutics (Duvall), OA
biology and single cell RNA sequencing (Maerz), and OA clinical care (Crofford). These successful scientists
cover the areas of expertise required for the proposed work, assuring high probability of the project’s success.
Terms: <Acceleration><Acetylgalactosamine><Address><Adrenal Cortex Hormones><Aging><Albumins><Amyloidosis><Animal Model><Animal Models and Related Studies><Anterior Cruciate Ligament><Architecture><Area><Arthralgia><Arthritis><Bioavailability><Biological Availability><Biology><Bone Spur><Cartilage><Cartilaginous Tissue><Cavia><Cell Body><Cell membrane><Cell-Extracellular Matrix><Cells><Chemicals><Chemistry><Chondrocytes><Clinical><Collagen Peptidase><Collagen Type II><Collagen-Degrading Enzyme><Complex><Corticoids><Corticosteroids><Cytoplasmic Membrane><Data><Degenerative Arthritis><Degenerative Disorder><Degenerative polyarthritis><Deterioration><Disease><Disease Progression><Disorder><Docking><Drug Carriers><Drug Kinetics><Drugs><ECM><Engineering / Architecture><Esteroproteases><Extracellular Matrix><FDA approved><Financial Hardship><Formulation><Future><Gene Expression><Gene Inactivation><Gene Silencing><Gene Targeting><Genes><Genetic><Genetic Medicine><Goals><Guinea Pigs><Guinea Pigs Mammals><Health Care Systems><Healthcare Systems><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hyperplasia><Hyperplastic><Hypertrophy><In Situ><In Vitro><Inflammation><Inflammatory><Injury><International><Intra-Articular Injections><Intraarticular Injections><Intravenous><Joint Pain><Joints><Knee><Lead><Leanness><Length><Length of Life><Ligands><Lipids><Liver><Liver Cells><Localized Disease><Longevity><MMP-13><MMP-13 gene product><MMP13 gene product><MMPs><Matrix Metalloproteinases><Medication><Mice><Mice Mammals><Modeling><Modification><Molecular><Murine><Mus><N acetylgalactosamine><NSAIDs><Nature><Non-Polyadenylated RNA><Non-Steroidal Anti-Inflammatory Agents><OB-cadherin><Osteoarthritis><Osteoarthrosis><Pain><Painful><Pathogenesis><Pb element><Penetration><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Phylogenetic Analysis><Phylogenetics><Physiologic Availability><Plasma Membrane><Polymers><Polyneuropathy><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Probability><Process><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA therapy><RNAi><Receptor Protein><Recommendation><Renal clearance function><Research><Resistance><Ribonucleic Acid><Risk><Scientist><Sequence-Specific Posttranscriptional Gene Silencing><Serum Albumin><Short interfering RNA><Signal Pathway><Single-Nucleus Sequencing><Site><Small Interfering RNA><Societies><Steroid Compound><Steroids><Stomach><Structure><System><Technology><Testing><Therapeutic><Therapeutic Effect><Thinness><Toxic effect><Toxicities><Traumatic Arthritis><Traumatic Arthropathy><Treatment Efficacy><United States><Work><amyloid disease><arthritic><bio-informatics pipeline><bioinformatics pipeline><cadherin-11><cell type><clinical care><clinical relevance><clinically relevant><collagenase><collagenase 3><cytokine><degenerative condition><degenerative disease><degenerative joint disease><design><designing><disability><drug/agent><efficacy testing><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><gastric><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes therapeutic><genes therapeutics><guinea pig model><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><hypertrophic arthritis><improved><injuries><innovate><innovation><innovative><interest><intervention efficacy><intravenous injection><joint damage><joint injury><joint trauma><lipid based nanoparticle><lipid nanoparticle><longevity gene><manufacture><matrix metalloproteinase-13><model of animal><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><natural aging><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-steroidal anti-inflammatory drugs><normal aging><normative aging><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nuclease><osteoarthritic><osteoblast cadherin><osteophyte><pain reduction><physical disability><physically disabled><physically handicapped><plasmalemma><polymer><polymeric><post-traumatic osteoarthritis><receptor><reduce pain><renal clearance><resistant><sNuc-Seq><scRNA-seq><siRNA><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><small molecule><snRNA sequencing><snRNA-seq><success><technology platform><technology system><therapeutic RNA><therapeutic efficacy><therapeutic gene><therapeutic target><therapy efficacy><transcriptional silencing><transcriptomics>