title: RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy.
abstract: BACKGROUND
  Neonatal gene therapy is a promising strategy for treating diseases diagnosed before or shortly after birth. Early and long-term expression of therapeutic proteins may limit the consequences of genetic mutations and result in a potential 'cure'. Adeno-associated viral vectors have shown promise in many areas of adult gene therapy but their properties have not been systematically investigated in the neonate.
  
  
  METHODS
  In these studies, using a constitutive promoter expressing luciferase, animals were administered one of ten serotypes of adeno-associated virus (AAV) on the second day of life. Examination of expression, organ growth and vector distribution, maintenance of expression and copy number were measured.
  
  
  RESULTS
  All serotypes demonstrated expression and, in general, transduction of all organs within 3 days, albeit with different biodistribution patterns and expression levels. The highest expression was detected with AAVrh10, whereas the lowest was detected with AAV4. Expression and genomes declined with growth over the first 10 weeks of life; thereafter, to day 100, expression and genomes remained relatively stable. With the highest expressing vectors, whole animal expression at 100 days declined to approximately 10% of that detected on the fifth day. AAVrh10 maintained the highest expression level and copy number throughout these studies.
  
  
  CONCLUSIONS
  The impact of tissue and organ growth on the stability of AAV expression will be important if neonatal gene transfer is to be considered as a modality for human gene therapy. Although all vectors did demonstrate expression, rh10 holds the greater promise of the vectors tested to maintain copy number in both mitotic and post-mitotic tissues.
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7054, USA.
authors.forename: Chuhong
authors.initials: C
authors.lastname: Hu
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Lipshutz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012703:Serotyping; D014018:Tissue Distribution; D019076:Transgenes / Q000502:physiology*
chemical_list: D008156:Luciferases
references.citation: Circ Res. 2006 Aug 18;99(4):e3-9
references.pmid: 16873720
references.citation: Gene Ther. 2005 Sep;12(18):1405-9
references.pmid: 15920463
references.citation: Mol Ther. 2010 Jan;18(1):118-25
references.pmid: 19861950
references.citation: Blood. 2003 Oct 1;102(7):2412-9
references.pmid: 12791653
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14082-7
references.pmid: 8943064
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13102-7
references.pmid: 12232044
references.citation: Blood. 2010 Jun 10;115(23):4678-88
references.pmid: 20335222
references.citation: J Biol Chem. 1996 Oct 25;271(43):26536-42
references.pmid: 8900123
references.citation: Mol Ther. 2008 Jun;16(6):1073-80
references.pmid: 18414476
references.citation: Pediatr Res. 2005 Dec;58(6):1143-7
references.pmid: 16306183
references.citation: J Virol. 1998 Mar;72(3):2224-32
references.pmid: 9499080
references.citation: J Virol. 2001 Aug;75(15):6969-76
references.pmid: 11435577
references.citation: Gene Ther. 2010 Apr;17(4):521-30
references.pmid: 20033064
references.citation: Mol Ther. 2002 Dec;6(6):745-58
references.pmid: 12498771
references.citation: J Clin Invest. 2008 Sep;118(9):3132-42
references.pmid: 18688285
references.citation: Hum Gene Ther. 2008 Dec;19(12):1359-68
references.pmid: 18795839
references.citation: Mol Ther. 2001 Mar;3(3):284-92
references.pmid: 11273769
references.citation: Mol Ther. 2004 Oct;10(4):671-8
references.pmid: 15451451
references.citation: Mol Ther. 2001 Oct;4(4):297-306
references.pmid: 11592831
references.citation: Blood. 2004 Jan 1;103(1):143-51
references.pmid: 12969967
references.citation: Liver. 2002 Oct;22(5):419-25
references.pmid: 12390477
references.citation: Blood. 2003 May 15;101(10):3924-32
references.pmid: 12531787
references.citation: Mod Rheumatol. 2004;14(1):18-24
references.pmid: 17028800
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11854-9
references.pmid: 12192090
references.citation: J Virol. 2006 Jun;80(12):6192-4
references.pmid: 16731960
references.citation: Mol Ther. 2002 Feb;5(2):141-53
references.pmid: 11829521
references.citation: Mol Ther. 2010 Mar;18(3):643-50
references.pmid: 19953081
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2112-6
references.pmid: 14766968
references.citation: Mol Ther. 2007 Sep;15(9):1677-85
references.pmid: 17565352
references.citation: J Virol. 2006 Jan;80(1):426-39
references.pmid: 16352567
references.citation: Mol Ther. 2008 Jun;16(6):1081-8
references.pmid: 18414478
references.citation: BMJ. 2001 Dec 8;323(7325):1331-5
references.pmid: 11739217
references.citation: J Surg Res. 2008 Jul;148(1):60-6
references.pmid: 18570932
references.citation: Mol Ther. 2006 Mar;13(3):528-37
references.pmid: 16413228
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10379-84
references.pmid: 10468616
references.citation: Gene Ther. 2007 Sep;14(18):1319-29
references.pmid: 17611587
references.citation: J Virol. 2004 Mar;78(6):3110-22
references.pmid: 14990730
references.citation: Gene Ther. 2007 Jul;14(13):989-97
references.pmid: 17251988
references.citation: Nat Genet. 1998 May;19(1):13-5
references.pmid: 9590280
references.citation: Mol Ther. 2005 Nov;12(5):867-75
references.pmid: 16085464
references.citation: J Virol. 1997 Mar;71(3):1776-83
references.pmid: 9032306
references.citation: Nat Biotechnol. 2010 Mar;28(3):271-4
references.pmid: 20190738
references.citation: Hum Gene Ther. 2009 Mar;20(3):267-81
references.pmid: 19257851
references.citation: Nat Genet. 1997 Jul;16(3):270-6
references.pmid: 9207793
references.citation: Mol Ther. 2008 Oct;16(10):1710-8
references.pmid: 18714307
references.citation: J Gene Med. 2004 Jun;6(6):663-72
references.pmid: 15170737
references.citation: Mech Dev. 2003 Jan;120(1):117-30
references.pmid: 12490302
references.citation: Science. 2003 Oct 17;302(5644):415-9
references.pmid: 14564000
references.citation: Mol Ther. 2009 Jul;17(7):1155-63
references.pmid: 19367256
references.citation: Hum Gene Ther. 1997 Nov 1;8(16):1891-900
references.pmid: 9382955
references.citation: Curr Gene Ther. 2007 Oct;7(5):403-10
references.pmid: 17979686
references.citation: Gene Ther. 2004 Oct;11 Suppl 1:S92-7
references.pmid: 15454963