Development of UTL-5b for Rheumatoid Arthritis: Mechanism of Action

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DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is one of the most common forms of arthritis, a potentially crippling autoimmune disease that affects more than two million Americans. At the present time, DMARD (Disease Modifying Anti- Rheumatic Drug) is an improved class of arthritis drugs over NSAID (Non-Steroidal Anti-Inflammatory Drug). We have synthesized and screened a series of innovative compounds, UTL series, as potential DMARDs. Among them, UTL-5b is the most promising compound for RA. UTL-5b was shown to significantly lower the elevated blood level of TNF-a and increase the survival rate in an LD100 sepsis animal model. In order to develop more information concerning the potential for UTL-5b to exert anti-arthritic effects, we propose to examine the therapeutic effects of UTL-5b in a CIA mouse model. Specific aims of this Phase I study are: (1) To synthesize 5 g of UTL-5b; (2) To develop, analyze, and optimize a formulation suitable for the proposed in vivo study; (3) To evaluate the anti-arthritic activity of UTL- 5b in the collagen-induced experimental arthritis model. Type II collagen-induced arthritis (CIA) in mice is an experimental model of arthritis with a number of pathological, immunological and genetic features in common with rheumatoid arthritis. A progressive, inflammatory arthritis develops in the majority of immunized animals, which is characterized clinically by erythema and edema, with affected paw width increases of typically 100%. A clinical scoring index has been developed to assess disease progression to joint distortion and spondylitis, and histopathology of affected joints reveals synovitis, pannus formation, and cartilage and bone erosion, which is represented by a validated index. Immunological laboratory findings include high antibody levels to type II collagen, and hyper- gammaglobulinemia. This model has been well established for testing of both biological and pharmacological agents for the treatment of rheumatoid arthritis. Both prophylactic and therapeutic administration of UTL-5b will be investigated in this study. In addition to an evaluation of the influence of UTL-5b on the pathological and immunological aspects of CIA, real-time PCR techniques will be used to examine the gene activity of LPS- induced TNF alpha factor (LITAF), mitogen activated protein kinase kinase kinase 2 (Map3k2), and JAK3 tyrosine-protein kinase (JAK3) in arthritic paws, lymph nodes and spleens In addition to the preliminary MOA study, which indicated that UTL-5b suppresses Map3K2, Jak3, and LITAF, the results from the proposed Phase I studies will be very useful in SBIR Phase II in designing further study protocols to clearly identify the detailed MOA of UTL-5b. This ultimate goal of the current proposal is to develop a small molecule TNF-a modulator as a significantly improved DMARD (disease modifying anti-arthritic drug). This phase 1 study will focus on a comprehensive collagen-induced arthritis animal study.