SBIR/STTR Award attributes
Rheumatoid arthritisRAis a chronic inflammatory disease that manifests as painful and swollen joints and subcutaneous nodulesamong other symptomsThe pathophysiology of the disease is autoimmune in nature and is believed to arise from genetic susceptibility coupled with specific environmental exposuresIn RAthe synovium is the primary site of inflammationsynovial macrophages increase significantly in patients with RArelative to normal synoviumand activated synovial macrophages are largely responsible for propagating inflammation and tissue destruction as they are the main producers of pro inflammatory cytokines such as TNFPresentlythere is not a cure for RAA relatively recent breakthrough has been the introduction of biologics such as anti TNFantibodiesas TNFplays a key role in the development and progression of RAAnti TNFbiologics are proven effective in treating patients previously unresponsive to other anti rheumatic therapiesbut not without limitationsSmall interfering RNAsiRNAe gTNFsiRNAoffers an attractive alternative to controlling pro inflammatory cytokines at the level of gene expressionWe recently developed a new TNFsiRNA solid lipid nanoparticle formulation that is efficacious in treating RA in a mouse model of collagen antibody induced arthritisHowevera key issue with siRNA therapy is the toxicity associated with the acute inflammatory response induced by the siRNAOur long term goal is to develop a safe and effective siRNA based RA therapyHerein we propose an innovative approach to minimize or eliminate the acute inflammatory response associated with siRNA therapy by including an anti inflammatory compound into our TNFsiRNA solid lipid nanoparticlesWe hypothesize that the proposed new TNFsiRNA solid lipid nanoparticles will not only address the acute inflammatory response associated with siRNA therapybut also be more efficacious than our nanoparticles incorporated with TNFsiRNA alone in controlling RA in a mouse modelWe propose two specific aims to test this hypothesisito identify the extent to which encapsulation of an anti inflammatory compound into our TNFsiRNA solid lipid nanoparticles will reduce the acute proinflammatory response induced by the siRNA nanoparticles in a mouse modeliito identify the extent to which our new TNFsiRNA solid lipid nanoparticles will control arthritis in a mouse model of collagen induced arthritisThe primary innovation of this project is the encapsulation of a known anti inflammatory compound into TNFsiRNA nanoparticles ito systemically inhibit the acute pro inflammatory response associated with siRNA therapyand iilocally at the chronic inflammation sites to enhance the efficacy of the TNFsiRNAOur project is significant because the proposed co delivery approachwhen proven successfulis expected to afford a new and effective treatment to RA and potentially other chronic inflammatory conditions as well Project NarrativeThe proposed research is relevant to public health because we aim at materializing a new therapeutic modality to improve the treatment of rheumatoid arthritis and other chronic inflammatory diseasesThereforethe proposed research is relevant to the NIH s mission of supporting research into the causetreatmentand prevention of arthritis and musculoskeletal and skin diseases
