PMID- 18461057
OWN - NLM
STAT- MEDLINE
DCOM- 20080804
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 16
IP  - 7
DP  - 2008 Jul
TI  - An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides 
      reduces inflammation in hepatitis and arthritis mouse models.
PG  - 1316-22
LID - 10.1038/mt.2008.85 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of inflammatory 
      diseases, including rheumatoid arthritis (RA), and anti-TNF-alpha drugs such as 
      etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are 
      a new class of drugs designed to induce therapeutically favorable splice variants 
      of targeted genes. In this work, we used locked nucleic acid (LNA)-based SSOs to 
      modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of 
      TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous 
      expression from the membrane-bound, functional form to a soluble, secreted form 
      (Delta7TNFR2). This decoy receptor protein accumulated in the circulation of 
      treated mice, antagonized TNF-alpha, and altered disease in two mouse models: 
      TNF-alpha-induced hepatitis and collagen-induced arthritis (CIA). This is the 
      first report of upregulation of the endogenous, circulating TNF-alpha antagonist 
      by oligonucleotide-induced splicing modulation.
FAU - Graziewicz, Maria A
AU  - Graziewicz MA
AD  - Ercole Biotech, Inc., Research Triangle Park, North Carolina 27709, USA.
FAU - Tarrant, Teresa K
AU  - Tarrant TK
FAU - Buckley, Brian
AU  - Buckley B
FAU - Roberts, Jennifer
AU  - Roberts J
FAU - Fulton, LeShara
AU  - Fulton L
FAU - Hansen, Henrik
AU  - Hansen H
FAU - Orum, Henrik
AU  - Orum H
FAU - Kole, Ryszard
AU  - Kole R
FAU - Sazani, Peter
AU  - Sazani P
LA  - eng
GR  - P01-GM059299/GM/NIGMS NIH HHS/United States
GR  - P01 GM059299-090001/GM/NIGMS NIH HHS/United States
GR  - 41AR054686-01/AR/NIAMS NIH HHS/United States
GR  - P01 GM059299/GM/NIGMS NIH HHS/United States
GR  - R41 AR054686/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080506
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Oligonucleotides)
RN  - 0 (RNA Splice Sites)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (locked nucleic acid)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/*drug therapy
MH  - Cell Line
MH  - Disease Models, Animal
MH  - Hepatitis/*drug therapy
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Oligonucleotides/*therapeutic use
MH  - *RNA Splice Sites
MH  - Receptors, Tumor Necrosis Factor, Type II/*genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/metabolism
MH  - Up-Regulation
PMC - PMC2671678
MID - NIHMS101268
EDAT- 2008/05/08 09:00
MHDA- 2008/08/05 09:00
PMCR- 2009/04/22
CRDT- 2008/05/08 09:00
PHST- 2008/05/08 09:00 [pubmed]
PHST- 2008/08/05 09:00 [medline]
PHST- 2008/05/08 09:00 [entrez]
PHST- 2009/04/22 00:00 [pmc-release]
AID - S1525-0016(16)32473-X [pii]
AID - 10.1038/mt.2008.85 [doi]
PST - ppublish
SO  - Mol Ther. 2008 Jul;16(7):1316-22. doi: 10.1038/mt.2008.85. Epub 2008 May 6.