PMID- 19848584
OWN - NLM
STAT- MEDLINE
DCOM- 20091110
LR  - 20221021
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Linking)
VI  - 19
IP  - 11
DP  - 2008 Nov
TI  - Efficient inhibition of hepatitis B virus replication in vivo, using polyethylene 
      glycol-modified adenovirus vectors.
PG  - 1325-31
AB  - Achieving safe delivery of anti-hepatitis B virus (HBV) RNA interference (RNAi) 
      effectors is an important objective of this gene-silencing technology. 
      Adenoviruses (Ads) have a natural tropism for the liver after systemic 
      administration, and are useful for delivery of expressed anti-HBV RNAi sequences. 
      However, a drawback of Ad vectors is diminished efficacy and toxicity that 
      results from stimulation of innate and adaptive immunity. To attenuate these 
      effects we used monomethoxy polyethylene glycol-succinimidyl propionate 
      (mPEG-SPA) to modify first-generation vectors that express an anti-HBV RNAi 
      effector. Efficient hepatocyte transduction and knockdown of HBV replication were 
      achieved after intravenous administration of 5 x 10(9) PEGylated or native 
      recombinant Ads to HBV transgenic mice. After the first injection, circulating 
      HBV viral particle equivalents (VPEs) remained low for 3 weeks and began to 
      increase after 5 weeks. A second dose of PEGylated anti-HBV Ad caused a less 
      sustained decrease in circulating VPEs, but no silencing after a second dose was 
      observed in animals treated with unmodified vector. Release of inflammatory 
      cytokines, including monocyte chemoattractant protein-1 (MCP-1), 
      interferon-gamma, interleukin-6, and tumor necrosis factor-alpha, was elevated in 
      animals receiving unmodified vectors. However, only a modest increase in MCP-1 
      was observed in mice that received a second dose of PEG Ads. Also, 
      polymer-conjugated vectors induced a weaker adaptive immune response and were 
      less hepatotoxic than their unmodified counterparts. Collectively, these 
      observations show that PEG modification of Ads expressing RNAi effectors improves 
      their potential for therapeutic application against HBV infection.
FAU - Crowther, Carol
AU  - Crowther C
AD  - Department of Molecular Medicine and Hematology, University of the Witwatersrand, 
      Johannesburg, South Africa.
FAU - Ely, Abdullah
AU  - Ely A
FAU - Hornby, Judith
AU  - Hornby J
FAU - Mufamadi, Steven
AU  - Mufamadi S
FAU - Salazar, Felix
AU  - Salazar F
FAU - Marion, Patricia
AU  - Marion P
FAU - Arbuthnot, Patrick
AU  - Arbuthnot P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Cytokines)
RN  - 0 (RNA, Small Interfering)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - EC 2.6.1.1 (Aspartate Aminotransferases)
RN  - EC 2.6.1.2 (Alanine Transaminase)
SB  - IM
MH  - Adenoviridae/*genetics
MH  - Alanine Transaminase/metabolism
MH  - Animals
MH  - Aspartate Aminotransferases/metabolism
MH  - Blotting, Northern
MH  - Cytokines/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - *Genetic Vectors
MH  - Hepatitis B virus/*physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Polyethylene Glycols/*chemistry
MH  - RNA Interference/physiology
MH  - RNA, Small Interfering/*physiology
MH  - Virus Replication/*physiology
EDAT- 2009/10/24 06:00
MHDA- 2009/11/11 06:00
CRDT- 2009/10/24 06:00
PHST- 2009/10/24 06:00 [entrez]
PHST- 2009/10/24 06:00 [pubmed]
PHST- 2009/11/11 06:00 [medline]
AID - 10.1089/hum.2008.066 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2008 Nov;19(11):1325-31. doi: 10.1089/hum.2008.066.