One siRNA pool targeting the λ constant region stops λ light-chain production and causes terminal endoplasmic reticulum stress

In systemic light-chain amyloidosis, lambda light chains produced by clonal plasma cells cause organ damage and early death. In pursuit of novel therapy, we developed 1 pool of short interfering RNA (siRNA) targeting the constant region of lambda light chains that substantially and promptly reduces lambda-light-chain production and secretion by human plasma cells regardless of sequence diversity. In clones producing intact immunoglobulin G (IgG) lambda antibodies (containing paired heavy and light chains), the secretion of intact antibodies is reduced, and all 3 branches of the unfolded protein response are activated by accumulation of unpaired IgG heavy chains in the endoplasmic reticulum (ER). Moreover, an ER stress response can then become terminal with effector caspase activity mediated in part by the transcription of the Bcl-2 homology 3 domain only family member NOXA. This pool of siRNA can be used to reduce pathological lambda-light-chain production and cause apoptosis in human plasma cells making intact IgG lambda antibodies.