PMID- 25790442
OWN - NLM
STAT- MEDLINE
DCOM- 20160229
LR  - 20150526
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 113
IP  - 6
DP  - 2015 Jun
TI  - Titrating haemophilia B phenotypes using siRNA strategy: evidence that 
      antithrombotic activity is separated from bleeding liability.
PG  - 1300-11
LID - 10.1160/TH14-06-0505 [doi]
AB  - Haemophilia A and B are characterised by a life-long bleeding predisposition, and 
      several lines of evidence suggest that risks of atherothrombotic events may also 
      be reduced. Establishing a direct correlation between coagulation factor levels, 
      thrombotic risks and bleeding propensity has long been hampered by an inability 
      to selectively and specifically inhibit coagulation factor levels. Here, the 
      exquisite selectivity of gene silencing combined with a gene knockout (KO) 
      approach was used to define the relative contribution of factor IX (fIX) to 
      thrombosis and primary haemostasis in the rat. Using a lipid nanoparticle (LNP) 
      formulation, we successfully delivered fIX siRNAs to the liver by intravenous 
      administration. The knockdown (KD) of target gene mRNA was achieved rapidly 
      (within 24 hour post-siRNA dosing), sustained (maintained for at least 7 days 
      post dosing) and not associated with changes in mRNA expression levels of other 
      coagulation factors. We found that intermediate levels of liver fIX mRNA 
      silencing (60-95 %) translating into a 50-99 % reduction of plasma fIX activity 
      provided protection from thrombosis without prolonging the cuticle bleeding time. 
      Over 99 % inhibition of fIX activity was required to observe increase in 
      bleeding, a phenotype confirmed in fIX KO rats. These data provide substantial 
      evidence of a participation of fIX in the mechanisms regulating thrombosis prior 
      to those regulating primary haemostasis, therefore highlighting the potential of 
      fIX as a therapeutic target. In addition, hepatic mRNA silencing using 
      LNP-encapsulated siRNAs may represent a promising novel approach for the chronic 
      treatment and prevention of coagulation-dependent thrombotic disorders in humans.
FAU - Metzger, Joseph M
AU  - Metzger JM
FAU - Tadin-Strapps, Marija
AU  - Tadin-Strapps M
AD  - Marija Tadin-Strapps, Department of Genetics and Pharmacogenomics, Merck Research 
      Laboratories, Merck & Co., Inc., 33 Avenue E Louis Pasteur, Boston, MA 02115, 
      USA, Tel.:+1 617 992 2339, E-mail: marija_tadin-strapps@merck.com.
FAU - Thankappan, Anil
AU  - Thankappan A
FAU - Strapps, Walter R
AU  - Strapps WR
FAU - DiPietro, Marti
AU  - DiPietro M
FAU - Leander, Karen
AU  - Leander K
FAU - Zhang, Zuo
AU  - Zhang Z
FAU - Shin, Myung K
AU  - Shin MK
FAU - Levorse, John
AU  - Levorse J
FAU - Desai, Kunal
AU  - Desai K
FAU - Xu, Yiming
AU  - Xu Y
FAU - Lai, KehDih
AU  - Lai K
FAU - Wu, Weizhen
AU  - Wu W
FAU - Chen, Zhu
AU  - Chen Z
FAU - Cai, Tian-Quan
AU  - Cai TQ
FAU - Jochnowitz, Nina
AU  - Jochnowitz N
FAU - Bentley, Ross
AU  - Bentley R
FAU - Hoos, Lizbeth
AU  - Hoos L
FAU - Zhou, Yuchen
AU  - Zhou Y
FAU - Sepp-Lorenzino, Laura
AU  - Sepp-Lorenzino L
FAU - Seiffert, Dietmar
AU  - Seiffert D
FAU - Andre, Patrick
AU  - Andre P
AD  - Patrick Andre, Cardiometabolic Disease, Merck & Co., Inc., Galloping Hill Road, 
      Kenilworth, NJ 07033, USA, Tel.:+1 908 740 7329, E-mail: Patrick.andre@merck.com.
LA  - eng
PT  - Journal Article
DEP - 20150319
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Chlorides)
RN  - 0 (Ferric Compounds)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 9001-28-9 (Factor IX)
RN  - U38V3ZVV3V (ferric chloride)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Chlorides
MH  - Disease Models, Animal
MH  - Factor IX/*genetics/metabolism
MH  - Ferric Compounds
MH  - Gene Expression Regulation
MH  - Genotype
MH  - Hemophilia B/blood/*genetics
MH  - Hemorrhage/blood/*genetics
MH  - Hemostasis/genetics
MH  - Liver/*metabolism
MH  - Male
MH  - Phenotype
MH  - *RNA Interference
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Small Interfering/*genetics/metabolism
MH  - *RNAi Therapeutics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Rats, Transgenic
MH  - Thrombosis/blood/chemically induced/genetics/*prevention & control
MH  - Time Factors
MH  - Transfection
OTO - NOTNLM
OT  - coagulation
OT  - factor fIX
OT  - haemostasis
OT  - siRNA
OT  - thrombosis
EDAT- 2015/03/20 06:00
MHDA- 2016/03/02 06:00
CRDT- 2015/03/20 06:00
PHST- 2014/06/11 00:00 [received]
PHST- 2015/01/20 00:00 [accepted]
PHST- 2015/03/20 06:00 [entrez]
PHST- 2015/03/20 06:00 [pubmed]
PHST- 2016/03/02 06:00 [medline]
AID - 14-06-0505 [pii]
AID - 10.1160/TH14-06-0505 [doi]
PST - ppublish
SO  - Thromb Haemost. 2015 Jun;113(6):1300-11. doi: 10.1160/TH14-06-0505. Epub 2015 Mar 
      19.