RNA interference (RNAi) is an evolutionary conserved mechanism for post transcriptional control ofprotein expression in which short double-stranded RNA target specific messenger RNA (mRNA) for degradation,thus inhibiting protein translation. siRNA has great potential to revolutionize medicine by enabling highly specificand efficient silencing of proteins involved in disease pathogenesis. Despite nearly 25 year of effort dedicated totranslating siRNA into a clinically relevant therapeutic, minimal clinical success has been achieved to date forbroad-based application due to lack of effective delivery technologies. Last year, FDA approved first-ever siRNAdrug developed by Alnylam® for an orphan disease, transthyretin-mediated amyloidosis. However, lipidic basedsiRNA delivery technology employed by Alnylam® limits the applications to liver diseases or treatments targetingliver involvement. Therefore, alternative delivery technologies are required to fully unleash the potential of siRNAand other nucleotides, e.g. mRNA, as effective therapeutics. To address these unmet medical needs, wedeveloped a new peptide (p5RHH)-based nucleotide delivery platform, which can deliver nucleotides (e.g. siRNAand mRNA) to sites of inflammation in vivo after systemic administration. This delivery platform protectsnucleotides in the blood stream and enables nucleotide endosomal escape for cytoplasmic delivery. Thebeneficial therapeutic effects have been demonstrated in preclinical animal models of atherosclerosis,necrotizing enterocolitis, pancreatic cancer, lung cancer, metastatic ovarian and uterine cancers, post traumaticosteoarthritis, and rheumatoid arthritis. In addition, this technology is patented and ready for commercialdevelopment. For product development, we will focus on anti-inflammatory treatment (anti-NFkB p5RHH-p65 siRNAnanoparticles) for rheumatoid arthritis, which is a chronic and debilitating inflammatory arthropathy. More than1.3 million Americans suffer from rheumatoid arthritis. The global drug market for rheumatoid arthritis is expectedto reach $30.7 billion dollars by 2025. We have demonstrated that p5RHH-p65 siRNA nanoparticles deliveredintravenously effectively silence the expression of p65 (i.e., canonical NF-kB) and suppress a broad array ofdownstream cytokine effectors in a mouse rheumatoid arthritis model of collagen antibody-mediatedinflammation. Consequently, arthritis is mitigated with minimal off-target molecular effects. The ultimate objectiveof this proposed work is to further develop p5RHH delivery platform into a clinical product for rheumatoid arthritisby targeting CD44 with following two specific aims. In the Specific Aim 1, we will establish an integrated andrapid hyaluronic acid coating process for the p5RHH-p65 siRNA nanoparticles that will enable moleculartargeting via CD44, which is highly abundant in joint synovium of rheumatoid arthritis patients. In Specific Aim 2,we will test the best performing nanoparticles in vivo in a conventional mouse model of rheumatoid arthritis.Completion of this Phase 1 study will yield enabling advances for Phase 2 IND preparations. Both small RNAs and message RNAs hold great potentials in treating diseases. However,
without the effective and safe delivery, the potentials cannot be unleashed. This proposed
study will bring a new and effective treatment for rheumatoid arthritis patients and avoid
bystander effects. 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Interleukin-1 ; IL-1 ; IL1 ; Interleukin I ; Lymphocyte-Stimulating Hormone ; Macrophage Cell Factor ; T Helper Factor ; lymphocyte activating factor ; Interleukin-6 ; B cell differentiation factor ; B cell stimulating factor 2 ; B-Cell Differentiation Factor ; B-Cell Differentiation Factor-2 ; B-Cell Stimulatory Factor-2 ; BCDF ; BSF-2 ; BSF2 ; HPGF ; Hepatocyte-Stimulating Factor ; Hybridoma Growth Factor ; IFN-beta 2 ; IFNB2 ; IL-6 ; IL6 Protein ; MGI-2 ; Myeloid Differentiation-Inducing Protein ; Plasmacytoma Growth Factor ; interferon beta 2 ; arthropathies ; Joint Diseases ; arthropathic ; arthropathy ; joint disorder ; Joints ; Leukocytes ; Blood leukocyte ; Leukocytes Reticuloendothelial System ; Marrow leukocyte ; White Blood Cells ; White Cell ; white blood cell ; white blood corpuscle ; Lipids ; Liver ; hepatic body system ; hepatic organ system ; Liver diseases ; Hepatic Disorder ; hepatic disease ; hepatopathy ; liver disorder ; Medicine ; Molecular Weight ; Mus ; Mice ; Mice Mammals ; 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Malignant Tumor of the Uterus ; Malignant Uterine Neoplasm ; Malignant Uterine Tumor ; Uterus Cancer ; base ; Organ ; Site ; Surface ; Benign ; Chronic ; Clinical ; Phase ; Biological ; Medical ; Chemicals ; Serum ; Blood Serum ; insight ; Malignant neoplasm of lung ; Malignant Tumor of the Lung ; Pulmonary Cancer ; Pulmonary malignant Neoplasm ; lung cancer ; uptake ; antiangiogenesis therapy ; Anti-Angiogenesis ; Antiangiogenesis ; anti-angiogenesis therapy ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Genetic ; Exposure to ; Morphology ; Shapes ; Inflammatory ; Malignant Pancreatic Neoplasm ; Pancreas Cancer ; Pancreatic Cancer ; pancreatic malignancy ; Malignant neoplasm of pancreas ; Intravenous ; Complex ; Stream ; Necrotizing Enterocolitis ; Best Practice Analysis ; Benchmarking ; American ; Lytotoxicity ; cytotoxicity ; experience ; membrane structure ; Membrane ; success ; protein activation ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; trait ; p65 ; Orphan Disease ; Rare Disorder ; orphan disorder ; Rare Diseases ; drug market ; validation studies ; Environmental Factor ; environmental risk ; Environmental Risk Factor ; Pathogenesis ; Reporting ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Modeling ; response ; Cardiac Toxicity ; Cardiotoxic ; Cardiotoxicity ; Metabolic syndrome ; Bystander Effect ; Short interfering RNA ; siRNA ; Small Interfering RNA ; Post-Transcriptional Gene Silencing ; Posttranscriptional Gene Silencing ; Quelling ; RNA Silencing ; RNAi ; Sequence-Specific Posttranscriptional Gene Silencing ; RNA Interference ; Malignant Ovarian Neoplasm ; Malignant Ovarian Tumor ; Malignant Tumor of the Ovary ; Ovary Cancer ; ovarian cancer ; Malignant neoplasm of ovary ; protein expression ; RNA Degradation ; Effectiveness ; preventing ; prevent ; CD44 ; MDU3 ; Pgp1 ; CD44 gene ; Small RNA ; Address ; Dose ; Mammalian Cell ; Molecular Target ; Post-Transcriptional Control ; post-transcriptional gene regulation ; posttranscriptional control ; posttranscriptional regulation ; Post-Transcriptional Regulation ; in vivo ; Ligand Binding ; Preparation ; Process ; Therapeutic Effect ; Development ; developmental ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; knock-down ; knockdown ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; targeted delivery ; site targeted delivery ; Population ; clinically relevant ; clinical relevance ; clinical application ; clinical applicability ; mouse model ; murine model ; combat ; FDA approved ; effective therapy ; effective treatment ; product development ; phase 1 study ; Phase I Study ; therapeutic RNA ; nucleic acid delivery ; in vivo evaluation ; in vivo testing ; nanoparticle delivery ; nano particle delivery ; nanoparticle delivered ; side effect ; RNA delivery ; therapeutically effective ;
