title: Preclinical development of siRNA therapeutics for AL amyloidosis.
abstract: 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.
authors.affiliation: Amyloid Treatment and Research Program, Alan and Sandra Gerry Amyloid Research Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Hovey
authors.forename: J E
authors.initials: JE
authors.lastname: Ward
authors.forename: P
authors.initials: P
authors.lastname: Soo Hoo
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Hara
authors.forename: L H
authors.initials: LH
authors.lastname: Connors
authors.forename: D C
authors.initials: DC
authors.lastname: Seldin
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000628:therapy*; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage; D010954:Plasmacytoma / Q000628:therapy; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D007147:Immunoglobulin Light Chains; D012333:RNA, Messenger; D034741:RNA, Small Interfering