PMID- 29107995
OWN - NLM
STAT- MEDLINE
DCOM- 20171128
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 11
DP  - 2017
TI  - The intratracheal administration of locked nucleic acid containing antisense 
      oligonucleotides induced gene silencing and an immune-stimulatory effect in the 
      murine lung.
PG  - e0187286
LID - 10.1371/journal.pone.0187286 [doi]
LID - e0187286
AB  - Locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) have the 
      potential to modulate the disease-related gene expression by the RNaseH-dependent 
      degradation of mRNAs. Pulmonary drug delivery has been widely used for the 
      treatment of lung disease. Thus, the inhalation of LNA-ASOs is expected to be an 
      efficient therapy that can be applied to several types of lung disease. Because 
      the lung has a distinct immune system against pathogens, the immune-stimulatory 
      effect of LNA-ASOs should be considered for the development of novel inhaled 
      LNA-ASOs therapies. However, there have been no reports on the relationship 
      between knock-down (KD) and the immune-stimulatory effects of inhaled LNA-ASOs in 
      the lung. In this report, LNA-ASOs targeting Scarb1 (Scarb1-ASOs) or negative 
      control LNA-ASOs targeting ApoB (ApoB-ASOs) were intratracheally administered to 
      mice to investigate the KD of the gene expression and the immune-stimulatory 
      effects in the lung. We confirmed that the intratracheal administration of 
      Scarb1-ASOs exerted a KD effect in the lung without a drug delivery system. On 
      the other hand, both Scarb1-ASOs and ApoB-ASOs induced neutrophilic infiltration 
      in the alveoli and increased the expression levels of G-CSF and CXCL1 in the 
      lung. The dose required for KD was the same as the dose that induced the 
      neutrophilic immune response. In addition, in our in vitro experiments, 
      Scarb1-ASOs did not increase the G-CSF or CXCL1 expression in primary lung cells, 
      even though Scarb1-ASOs exerted a strong KD effect. Hence, we hypothesize that 
      inhaled LNA-ASOs have the potential to exert a KD effect in the lung, but that 
      they may be associated with a risk of immune stimulation. Further studies about 
      the mechanism underlying the immune-stimulatory effect of LNA-ASOs is necessary 
      for the development of novel inhaled LNA-ASO therapies.
FAU - Uemura, Yasunori
AU  - Uemura Y
AUID- ORCID: 0000-0002-9366-4652
AD  - Immunology & Allergy R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 
      Nagaizumi-cho, Shizuoka, Japan.
FAU - Hagiwara, Kenji
AU  - Hagiwara K
AD  - Innovative Technology Labs, Research Functions Unit, R&D Division, Kyowa Hakko 
      Kirin Co., Ltd., Machida, Tokyo, Japan.
FAU - Kobayashi, Katsuya
AU  - Kobayashi K
AD  - Immunology & Allergy R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 
      Nagaizumi-cho, Shizuoka, Japan.
LA  - eng
PT  - Journal Article
DEP - 20171106
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Oligonucleotides)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (locked nucleic acid)
SB  - IM
MH  - Animals
MH  - Female
MH  - Gene Silencing/*drug effects
MH  - Lung/cytology/*drug effects/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oligonucleotides/*administration & dosage/chemistry/pharmacology
MH  - Oligonucleotides, Antisense/*chemistry
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC5673232
COIS- Competing Interests: The authors declare the following interests: YU, KH, and KK 
      are affiliated with the commercial company, Kyowa Hakko Kirin. There are no 
      patents, products in development, or marketed products to declare. This does not 
      alter the authors' adherence to all PLOS ONE policies on sharing data and 
      materials.
EDAT- 2017/11/07 06:00
MHDA- 2017/11/29 06:00
PMCR- 2017/11/06
CRDT- 2017/11/07 06:00
PHST- 2017/02/24 00:00 [received]
PHST- 2017/10/17 00:00 [accepted]
PHST- 2017/11/07 06:00 [entrez]
PHST- 2017/11/07 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/11/06 00:00 [pmc-release]
AID - PONE-D-17-07600 [pii]
AID - 10.1371/journal.pone.0187286 [doi]
PST - epublish
SO  - PLoS One. 2017 Nov 6;12(11):e0187286. doi: 10.1371/journal.pone.0187286. 
      eCollection 2017.