The antisense approach in amyloid light chain amyloidosis: identification of monoclonal Ig and inhibition of its production by antisense oligonucleotides in in vitro and in vivo models.
Primary amyloid L chain (AL) amyloidosis is a plasma cell disorder in which depositions of AL cause progressive organ failure. The lack of effective therapies for this fatal disease prompts exploration of newer treatment avenues. We have investigated the application of antisense oligonucleotides (AS) for the inhibition of monoclonal Ig production. The monoclonal L chain was identified by using primers designed for amplifying the human lambda Ig V (Vlambda) region. We demonstrated that AS against L chain complementarity-determining regions inhibited the production of L chain in vitro. RPMI 8226 myeloma cells injected in SCID mice developed s.c. tumors. RT-PCR analysis showed Vlambda mRNA expression in the tumors. In addition, the presence of human Ig in the sera of mice given injection of RPMI 8226 cells was confirmed by ELISA. Administration of AS inhibited the expression of Vlambda mRNA in the s.c. tumors and decreased the concentration of L chain in serum. Therefore, we have shown that it is possible to determine the sequence of Vlambda mRNA and design specific complementary oligonucleotides, suggesting that treatment with Vlambda antisense could represent a rational novel approach to improve treatment outcome in AL amyloidosis.
Ohno
Satoko
S
First Department of Internal Medicine and Department of Neurology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yoshimoto
Mitsuru
M
Honda
Saho
S
Miyachi
Sae
S
Ishida
Tadao
T
Itoh
Fumio
F
Endo
Takao
T
Chiba
Susumu
S
Imai
Kohzoh
K
D000595:Amino Acid Sequence; D000682:Amyloid / Q000276:immunology*; D000686:Amyloidosis / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D001483:Base Sequence; D005784:Gene Amplification; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015552:Injections, Intralesional; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010265:Paraproteinemias / Q000235:genetics / Q000276:immunology / Q000628:therapy; D012333:RNA, Messenger / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000682:Amyloid; D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains; D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger