Inhibition of Bence-Jones protein synthesis by RNA interference (49.30)

Abstract A main contributing factor to the morbidity and mortality of patients with multiple myeloma results from the pathologic deposition as casts within renal tubules of monoclonal Ig light chains, i.e., Bence-Jones proteins (BJP). As an alternative to plasma cell chemotherapy to reduce BJP synthesis and thus prevent myeloma (cast) nephropathy we have investigated another means to achieve this objective, namely, RNA interference (RNAi). Experimentally, we have stably transfected the SP2/O mouse myeloma cells with a construct containing the V, J, and C region of a λ BJP (Wil) under the control of a CMV promoter and have shown that they constitutively express measurable quantities of mRNA and protein Wil. Treatment of these cells with synthetic, small double stranded RNA based on the Wil protein sequence reduced target mRNA levels by 2-fold at 48 h and protein production by 30% at 72 h, as compared with controls. These data provide conclusive evidence that RNAi can effectively reduce BJP production in vitro and provide the base for testing the clinical potential of this strategy using a relevant in vivo murine model of myeloma (cast) nephropathy.