Amyloid Treatment and Research Program, Alan and Sandra Gerry Amyloid Research Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
Gene Ther. 2011 Dec;18(12):1150-6. doi: 10.1038/gt.2011.69. Epub 2011 May 12.
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.
淀粉样轻链 (AL) 淀粉样变性是一种罕见的血液学疾病，其特征是异常折叠的单克隆免疫球蛋白 (Ig) 轻链 (LC) 作为纤维状蛋白沉积物积累。目前的治疗方法包括细胞毒性化疗和免疫调节治疗，旨在杀死产生 LCs 的浆细胞，但对其他细胞类型有很大的毒性。我们设计了针对淀粉样 LC 信使 RNA (mRNA) 的小干扰 RNA (siRNA)，以降低淀粉样前体蛋白的表达。使用纳摩尔浓度的 siRNA，我们已经以剂量依赖的方式抑制了转染细胞中 LC 的合成。此外，在 AL 淀粉样变性的体内浆细胞瘤小鼠模型中，我们已经证明这些 siRNA 可以显著降低局部产生和循环中的 LC 水平。该模型系统突出了 siRNA 治疗 AL 淀粉样变性的治疗潜力。
