Treatment of Idiopathic Myelofibrosis Employing siRNA for Heat Shock Protein 47 (siRNA/HSP47) Encapsulated in Liposomes.

Abstract

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by bone marrow (BM) fibrosis, splenomegaly, extramedurally hematopoiesis and anemia. At present, there is no curative treatment available for this disease except allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the high therapy-related mortality of allo-HSCT, even in reduced-intensity transplantation, could not be ignored. We report a novel approach for the treatment of IMF, utilizing siRNA for a collagen specific chaperon, heat shock protein 47 (HSP47) encapsulated in liposomes (lip-siRNA/HSP47). We first confirmed suppression of HSP47 in NIH3T3 murine fibroblast cell line and primary murine BM fibroblasts, and collagen secretion from these cells by siRNA/HSP47. We next treated thrombopoietin (TPO) transgenic mice exhibiting IMF like feature (Shimoda K, Harada M et al. Leuk Res 29, 761–769, 2005; Am J Hematol 82, 802–806, 2007). In these mice, treatment by intravenous injection of lip-siRNA/HSP47 resulted in histological resolution of myelofibrosis associated with apoptotic death of BM fibroblasts, and improvement of anemia and splenomegaly. Thus, lip-siRNA/HSP47 therapy may be a promising treatment for IMF.