Despite remarkable improvements in the prognosis of patients with SLE, this disease is still accompanied by significant morbidity and mortality and many of the standard treatments are associated with significant side effects indicating the need for the development of effective therapies. Recent studies have recently demonstrated that T cells from lupus-prone mice exhibit increased activation of ROCK2 and that inhibiting this kinase can be effective in ameliorating disease in two distinct murine models of lupus suggesting that targeting this pathway may be of broad clinical utility in lupus. Given that inhibition of ROCK activity is one of the key mechanisms responsible for the pleiotropic effects of statins in the present proposal we will explore the hypothesis that the ability of statins to interfere with ROCK activation, if harnessed effectively, can exert beneficial effects in SLE. Furthermore, because statins and ROCK inhibitors target two different steps in this signaling cascade we will investigate the possibility that combination therapy with a statin and a ROCK inhibitor will synergize in inhibiting ROCK2 and be more effective than monotherapy at ameliorating immune and clinical aspects of lupus. Specifically, we will: 1) Assess whether simvastatin inhibits ROCK2 activation in T cells from SLE patients in vitro and whether it can synergize with Fasudil, a ROCK inhibitor and 2) Evaluate whether administration of simvastatin to SLE patients can effectively interfere with ROCK2 activation.
The information obtained from these studies will enable us to determine whether, as presently used, statin therapy is only modestly effective in inhibiting the RhoA-ROCK pathway and whether combination therapy of a statin and a ROCK inhibitor can be more effective in targeting this pathway than monotherapy. Given that ROCK inhibitors are already in clinical use for the treatment of other disorders and have demonstrated only minimal side effects, at the end of this series of studies, this knowledge could be rapidly translated intoa novel therapeutic regimen for the treatment of SLE. The studies outlined in this proposal will enable the development of novel assays that will allow monitoring of the ROCK pathway in SLE patients and facilitate the optimization of treatment regimens for individual SLE patients in clinical trials of these agents, allowing a 'treat-to-target approach with a biomarker as the target.
|Isgro, Josephine; Gupta, Sanjay; Jacek, Elzbieta et al. (2013) Enhanced rho-associated protein kinase activation in patients with systemic lupus erythematosus. Arthritis Rheum 65:1592-602|