A Novel Probiotic for the Treatment of Rheumatoid Arthritis

Project Summary Our goal is to develop a novel L lactis probiotic based therapeutic for the treatment of rheumatoid arthritis RA RA is a chronic systemic inflammatory disorder affecting as much as worldwide and as much as of the US population The exact frequencies depend on geographical origin and gender women being three times more affected than men While many organs are affected the main targets of RA are synovial joints and approximately half of the affected patients become disabled over the progression of the disease Treatment of RA remains a significant unmet medical need Since TNF is a major facilitator of disease progression TNF antagonists can effectively diminish inflammation and attenuate destruction of cartilage and bone However a large number of patients either fail to respond to or relapse with anti TNF therapy In addition prolonged treatment with TNF antagonists can have deleterious side effects making patients more susceptible to opportunistic infections Immunotherapy for autoimmune disorders is also especially attractive for correcting inflammatory diseases without having to resort to immunosuppressive drug therapies The two main goals of such an approach are to switch off the immune response against the host s own tissues and maximally balance the relationships between effector cells of different lineages to prevent relapses of chronic inflammation Originally conceived as a diarrheal vaccine for humans when using Salmonella vaccine vectors we found colonization factor antigen I CFA I from human enterotoxigenic E coli ETEC is potently effective in preventing and treating experimental models for arthritis and multiple sclerosis In fact purified CFA I fimbriae when given orally or nasally and administered in lieu of live Salmonella CFA I as a source of fimbriae can effectively attenuate inflammation without the associated side effects from Salmonella To avoid efforts and costs associated with producing sufficient quantities of recombinant CFA I fimbriae and to increase the PK PD properties of CFA I fimbriae following oral administration we have successfully engineered a Lactococcus lactis strain to express CFA I fimbriae L lactis CFA I Similar to purified CFA I fimbriae this L lactis CFA I is effective in preventing and treating experimental arthritis The next step in the development process is to produce a food grade L lactis CFA I strain called VTC CFA for clinic development The specific aims of this proposal are to generate L lactis clones expressing CFA I from a genome integrated operon select a VTC CFA clinical candidate based on growth rate CFA I expression and stability and demonstrate CD regulatory T cell expansion with oral treatment of VTC CFA in normal mice Successful commercialization of VTC CFA will ultimately provide a profound front line medical advancement in the treatment of RA Project Narrative RA is a progressive chronic autoimmune disease characterized by inflammation and pain of the joints RA is a chronic systemic inflammatory disorder affecting as much as worldwide and as much as of the US population The exact frequencies depend on geographical origin and gender women being three times more affected than men This project aims to develop a novel L lactis probiotic expressing colonization factor antigen I CFA I for the treatment of RA Successful commercialization would ultimately provide a profound front line medical advancement in the treatment of RA