Clinical Application of Cell Cycle Control Therapy to Rheumatoid Arthritis

点击翻译按钮获取中文摘要

Forced expression of a cyclin-dependent kinase inhibitor (CDKI) gene, p16^<INK4a> or p21^<Cip1> in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Subsequently, we have studied molecular mechanism and application of cell cycle control for treatment of rheumatoid arthritis (RA).1) Anti-inflammatory effects of CDKI gene therapy : CDKI gene therapy suppressed expression of inflammatory mediators and proteinases via both CDK inhibition dependent- and CDK inhibition independent-pathways.2) Improvement of gene transfer efficacy by modified adenovirses : Because of a fatal accident by gene therapy using adenovirus vector, safety of adenovirus vector is strongly demanded. Efficacies of gene transfer to rheumatoid synovial fibroblasts (RSF) by type 5 adenoviruses (Ad5) vector were improved by modification fiber-coat proteins expressing Arg-Gly-Asp (RGD) motif or by Ad5 carrying a part of the fiber molecule of adenovirus serotype 35. Comparing with non- … More modified Ad5, fewer quantities of these fiber-modified Ad5 vectors were required to treat synovitis of RA animal model.3) Development of CDKI-'biologics : CDKI therapy without viral vector was studied. Protein can be delivered intracellularly if it HIV transmembrane domain (TAT) is conjugated. TAT-conjugated p16^<INK4a> fusion protein inhibited RSF proliferation, and therapeutic effects for RA animal model is investigated.4) Synthetic small molecule (sm)-CDKI for treatment of RA : Some synthetic sm-CDKI compounds were effective for synovitis of RA animal model, and we have applied patents of two sm-CDKI compounds for RA therapy.5) Selective p16^<INK4a> induction in RSF by p21^<Cip1> : Forced expression of p21^<Cip1> in RSF induced p16^<INK4a> expression. This p16^<INK4a> induction was not observed in the other fibroblasts. Using fluorescent differential display or GeneChip (Affimetrix) techniques, we screened a group of molecules that might be involved in the p21^<Cip1>-p16^<INK4a> pathway. One of the candidate molecules, that is related to pregnancy, increased p16^<INK4a> promoter activity Less