PMID- 37256266
OWN - NLM
STAT- MEDLINE
DCOM- 20230705
LR  - 20230705
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 211
IP  - 2
DP  - 2023 Jul 15
TI  - Antisense Oligonucleotide Therapy Decreases IL-1beta Expression and Prolongs 
      Survival in Mutant Nlrp3 Mice.
PG  - 287-294
LID - 10.4049/jimmunol.2200550 [doi]
AB  - Antisense oligonucleotides (ASOs) are a novel therapeutic strategy that targets a 
      specific gene and suppresses its expression. The cryopyrin-associated periodic 
      syndromes (CAPS) are a spectrum of autoinflammatory diseases characterized by 
      systemic and tissue inflammation that is caused by heterozygous gain-of-function 
      mutations in the nucleotide-binding and oligomerization domain-like receptor 
      (NLR) family pyrin domain containing 3 (NLRP3) gene. The aim of this study was to 
      investigate the efficacy of an Nlrp3-specific ASO treatment in CAPS. An 
      Nlrp3-specific ASO was designed and tested in murine cell lines and bone 
      marrow-derived macrophages (BMDMs) from wild-type and CAPS mouse models. Nlrp3 
      knock-in mice were treated in vivo with Nlrp3-specific ASO, survival was 
      monitored, and expression of organ-specific Nlrp3 and IL-1beta was measured. 
      Nlrp3-specific ASO treatment of murine cell lines and BMDMs showed a significant 
      downregulation of Nlrp3 and mature IL-1beta protein expression. Ex vivo treatment of 
      Nlrp3 mutant mouse-derived BMDMs with Nlrp3-specific ASO demonstrated 
      significantly reduced IL-1beta release. In vivo, Nlrp3-specific ASO treatment of 
      Nlrp3 mutant mice prolonged survival, reduced systemic inflammation, and 
      decreased tissue-specific expression of Nlrp3 and mature IL-1beta protein. The 
      results of this study demonstrate that Nlrp3-specific ASO treatment downregulates 
      Nlrp3 expression and IL-1beta release in CAPS models, suggesting ASO therapy as a 
      potential treatment of CAPS and other NLRP3-mediated diseases.
CI  - Copyright (c) 2023 by The American Association of Immunologists, Inc.
FAU - Kaufmann, Benedikt
AU  - Kaufmann B
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
AD  - Klinik und Poliklinik fur Chirurgie, Klinikum rechts der Isar, Technische 
      Universitat Munchen, Munich, Germany.
FAU - de Los Reyes Jimenez, Marta
AU  - de Los Reyes Jimenez M
AD  - Secarna Pharmaceuticals GmbH & Co. KG, Planegg/Martinsried, Germany.
FAU - Booshehri, Laela M
AU  - Booshehri LM
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
FAU - Onyuru, Janset
AU  - Onyuru J
AUID- ORCID: 0000-0003-3924-8487
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
FAU - Leszczynska, Aleksandra
AU  - Leszczynska A
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
FAU - Uri, Anna
AU  - Uri A
AD  - Secarna Pharmaceuticals GmbH & Co. KG, Planegg/Martinsried, Germany.
FAU - Michel, Sven
AU  - Michel S
AUID- ORCID: 0000-0003-3604-3187
AD  - Secarna Pharmaceuticals GmbH & Co. KG, Planegg/Martinsried, Germany.
FAU - Klar, Richard
AU  - Klar R
AUID- ORCID: 0000-0001-6625-794X
AD  - Secarna Pharmaceuticals GmbH & Co. KG, Planegg/Martinsried, Germany.
FAU - Jaschinski, Frank
AU  - Jaschinski F
AD  - Secarna Pharmaceuticals GmbH & Co. KG, Planegg/Martinsried, Germany.
FAU - Feldstein, Ariel E
AU  - Feldstein AE
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
AD  - Rady Children's Hospital-San Diego, San Diego, CA.
FAU - Broderick, Lori
AU  - Broderick L
AUID- ORCID: 0000-0001-6147-7097
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
AD  - Rady Children's Hospital-San Diego, San Diego, CA.
FAU - Hoffman, Hal M
AU  - Hoffman HM
AD  - Department of Pediatrics, University of California San Diego, La Jolla, CA.
AD  - Rady Children's Hospital-San Diego, San Diego, CA.
LA  - eng
GR  - R01 DK113592/DK/NIDDK NIH HHS/United States
GR  - R01 AA024206/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Inflammasomes)
RN  - 0 (Carrier Proteins)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Nlrp3 protein, mouse)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
MH  - Inflammasomes/metabolism
MH  - *Cryopyrin-Associated Periodic Syndromes/genetics
MH  - Inflammation
MH  - Carrier Proteins/genetics
MH  - Interleukin-1beta/metabolism
EDAT- 2023/05/31 13:12
MHDA- 2023/07/05 06:42
CRDT- 2023/05/31 10:41
PHST- 2022/08/01 00:00 [received]
PHST- 2023/05/08 00:00 [accepted]
PHST- 2023/07/05 06:42 [medline]
PHST- 2023/05/31 13:12 [pubmed]
PHST- 2023/05/31 10:41 [entrez]
AID - 263844 [pii]
AID - 10.4049/jimmunol.2200550 [doi]
PST - ppublish
SO  - J Immunol. 2023 Jul 15;211(2):287-294. doi: 10.4049/jimmunol.2200550.