PMID- 19407801
OWN - NLM
STAT- MEDLINE
DCOM- 20090618
LR  - 20231213
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 458
IP  - 7242
DP  - 2009 Apr 30
TI  - Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic 
      inflammation.
PG  - 1180-4
LID - 10.1038/nature07774 [doi]
AB  - Gene silencing by double-stranded RNA, denoted RNA interference, represents a new 
      paradigm for rational drug design. However, the transformative therapeutic 
      potential of short interfering RNA (siRNA) has been stymied by a key 
      obstacle-safe delivery to specified target cells in vivo. Macrophages are 
      particularly attractive targets for RNA interference therapy because they promote 
      pathogenic inflammatory responses in diseases such as rheumatoid arthritis, 
      atherosclerosis, inflammatory bowel disease and diabetes. Here we report the 
      engineering of beta1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient 
      oral delivery vehicles that potently silence genes in mouse macrophages in vitro 
      and in vivo. Oral gavage of mice with GeRPs containing as little as 20 microg 
      kg(-1) siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted 
      its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and 
      lung, and lowered serum Tnf-alpha levels. Screening with GeRPs for inflammation 
      genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 
      (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, 
      silencing Map4k4 in macrophages in vivo protected mice from 
      lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and 
      interleukin-1beta production. This technology defines a new strategy for oral 
      delivery of siRNA to attenuate inflammatory responses in human disease.
FAU - Aouadi, Myriam
AU  - Aouadi M
AD  - Program in Molecular Medicine, University of Massachusetts Medical School, 
      Worcester, Massachusetts 01605, USA.
FAU - Tesz, Gregory J
AU  - Tesz GJ
FAU - Nicoloro, Sarah M
AU  - Nicoloro SM
FAU - Wang, Mengxi
AU  - Wang M
FAU - Chouinard, My
AU  - Chouinard M
FAU - Soto, Ernesto
AU  - Soto E
FAU - Ostroff, Gary R
AU  - Ostroff GR
FAU - Czech, Michael P
AU  - Czech MP
LA  - eng
GR  - R01 DK060837-01A1/DK/NIDDK NIH HHS/United States
GR  - R01 DK030898-26/DK/NIDDK NIH HHS/United States
GR  - R01 DK060837/DK/NIDDK NIH HHS/United States
GR  - DK 30898/DK/NIDDK NIH HHS/United States
GR  - R37 DK030898/DK/NIDDK NIH HHS/United States
GR  - DK 32520/DK/NIDDK NIH HHS/United States
GR  - R01 DK030898/DK/NIDDK NIH HHS/United States
GR  - P30 DK032520-25/DK/NIDDK NIH HHS/United States
GR  - DK 60837/DK/NIDDK NIH HHS/United States
GR  - P30 DK032520/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Glucans)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - *Drug Delivery Systems
MH  - Enzyme Activation/drug effects
MH  - *Gene Silencing
MH  - Glucans/metabolism
MH  - Inflammation/genetics/*prevention & control
MH  - Interleukin-1beta/biosynthesis
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Macrophages/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/metabolism
MH  - Organ Specificity
MH  - Protein Serine-Threonine Kinases/*deficiency/*genetics/metabolism
MH  - RNA, Small Interfering/*administration & dosage/genetics/metabolism
MH  - Substrate Specificity
MH  - Tumor Necrosis Factor-alpha/biosynthesis/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
MH  - NF-kappaB-Inducing Kinase
PMC - PMC2879154
MID - NIHMS205041
EDAT- 2009/05/02 09:00
MHDA- 2009/06/19 09:00
PMCR- 2010/06/01
CRDT- 2009/05/02 09:00
PHST- 2008/11/04 00:00 [received]
PHST- 2009/01/06 00:00 [accepted]
PHST- 2009/05/02 09:00 [entrez]
PHST- 2009/05/02 09:00 [pubmed]
PHST- 2009/06/19 09:00 [medline]
PHST- 2010/06/01 00:00 [pmc-release]
AID - nature07774 [pii]
AID - 10.1038/nature07774 [doi]
PST - ppublish
SO  - Nature. 2009 Apr 30;458(7242):1180-4. doi: 10.1038/nature07774.