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

Abstract:

:In systemic light-chain amyloidosis, λ 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 λ light chains that substantially and promptly reduces λ-light-chain production and secretion by human plasma cells regardless of sequence diversity. In clones producing intact immunoglobulin G (IgG) λ 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 λ-light-chain production and cause apoptosis in human plasma cells making intact IgGλ antibodies.

journal_name

Blood

journal_title

Blood

authors

Zhou P,Ma X,Iyer L,Chaulagain C,Comenzo RL

doi

10.1182/blood-2013-10-535187

subject

Has Abstract

pub_date

2014-05-29 00:00:00

pages

3440-51

issue

22

eissn

0006-4971

issn

1528-0020

pii

blood-2013-10-535187

journal_volume

123

pub_type

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