Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.

Recent evidence from the study of different amyloidogenic proteins challenges the dogma that tissue damage is solely the result of amyloid fibril deposition. To examine whether amyloidogenic human immunoglobulin light chains (LCs) may cause acute toxic effects prior to the development of fibrillar tissue deposits in vivo, we have generated amyloidogenic LC-expressing cell lines and transplanted them into mice. A full length lambda-6 light chain was cloned from cDNA prepared from bone marrow of a patient with aggressive multi-organ AL amyloidosis. The LC was subcloned into an expression vector with a CMV promoter and transfected into SP2/0 plasmacytoma cells. Stably transfected cells were injected into syngeneic Balb/c and RAG−/− mice. Four-six weeks later, echocardiograms were performed and the mice were euthanized and serum, urine, and tissues were collected. Mice injected with LC-producing cells, but not control untransfected SP2/0 cells, had detectable circulating human LC in their serum, and 6 of 9 RAG−/− mice excreted LC and albumin in the urine. These mice had evidence of bradycardia by echocardiography, with 4 of 12 mice having heart rates lower than 500 bpm while no controls had heart rates that low, and upregulation of markers of cell stress in the heart. In the kidney, there was evidence of amorphous protein deposits and early glomerulopathy by electron microscopy in two mice examined, but no fibril deposition. Thus, short-term expression of human amyloidogenic LC in mice in vivo produces alterations in heart and kidney function prior to the development of fibrillar deposits.