Gene delivery to the juvenile mouse liver using AAV2/8 vectors

Molecular Therapy : the Journal of the American Society of Gene Therapy
Sharon C CunninghamIan E Alexander

Abstract

Recombinant adeno-associated viral (rAAV) vectors have shown promise for use in liver-targeted gene delivery, but their effects have not been extensively investigated in the immature liver. Understanding the impact of liver growth on the efficacy of transduction is essential, because many monogenic liver diseases that are amenable to gene therapy will require treatment early in life. Here we show that rAAV2/8 transduces the neonatal mouse liver with high efficiency. With just one doubling in liver weight, however, there is a rapid reduction in vector genome numbers, irrespective of form, and the loss of episomal vector is almost complete by 2 weeks. Stable transgene expression is observed in a small percentage of hepatocytes, often in two- to eight-cell clusters, suggestive of genomic integration. Delivery at serially older ages was associated with progressively improved episome persistence and transgene expression. Vector re-administration was possible following initial neonatal administration, albeit at reduced efficacy because of an anticapsid humoral immune response. We also found that intraperitoneal (i.p.) delivery of rAAV2/8 was highly effective at all ages, and that promoter selection is the critical determinant of the ...Continue Reading

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Citations

Feb 9, 2012·Journal of Inherited Metabolic Disease·Dwight D Koeberl
Mar 10, 2012·Journal of Inherited Metabolic Disease·Ian E AlexanderSharon C Cunningham
Jul 2, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Allison P DaneIan E Alexander
Oct 29, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Randy J Chandler, Charles P Venditti
Apr 16, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Chia-Ling GauGerald S Lipshutz
Apr 23, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sharon C CunninghamIan E Alexander
Apr 15, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Wai Han YiuJanice Y Chou
Jun 2, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Citra N Z MattarJerry K Y Chan
Aug 4, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lili WangJames M Wilson
Mar 10, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sharon C CunninghamIan E Alexander
Jul 5, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Eun K LeeGerald S Lipshutz
Aug 2, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jasmina LovricMauro Giacca
Jan 6, 2011·Human Gene Therapy·Peter BellJames M Wilson
Nov 22, 2011·Human Gene Therapy·Lili WangJames M Wilson
Jun 14, 2014·Proceedings of the National Academy of Sciences of the United States of America·Szun Szun TayDavid G Bowen
May 17, 2014·Gene Therapy·S M O'NeillM P Reilly
Jun 4, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Chuhong HuGerald S Lipshutz
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Aug 21, 2015·Current Opinion in Pharmacology·Leszek LisowskiIan Edward Alexander
Feb 13, 2016·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dustin J LandauDwight D Koeberl
Jan 30, 2009·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Jerome M LaurenceAlexandra F Sharland
May 27, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sharon C CunninghamIan E Alexander
Dec 7, 2013·Clinical & Developmental Immunology·Eithne C CunninghamG Alex Bishop
Jul 23, 2011·Molecular Genetics and Metabolism·Peter BellJames M Wilson
Sep 17, 2014·Journal of Inherited Metabolic Disease·Elizabeth D Brooks, Dwight D Koeberl
Jan 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Chuhong HuGerald S Lipshutz
Nov 30, 2016·Human Gene Therapy·Lisa M KattenhornSamuel C Wadsworth

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