Our study aimed to target adenoviral gene therapy to the uteroplacental circulation of pregnant guinea pigs in order to develop a novel therapy for fetal growth restriction. Four methods of delivery of an adenovirus encoding β-galactosidase (Ad.LacZ) were evaluated: intravascular injection using phosphate-buffered saline (PBS) into (1) uterine artery (UtA) or (2) internal iliac artery or external administration in (3) PBS or (4) pluronic F-127 gel (Sigma Aldrich). Postmortem examination was performed 4 to 7 days after gene transfer. Tissue transduction was assessed by X-gal histochemistry and enzyme-linked immunosorbent assay. External vascular application of the adenovirus vector in combination with pluronic gel had 91.7% success rate in terms of administration (85% maternal survival) and gave the best results for maternal/fetal survival and local transduction efficiency without any spread to maternal or fetal tissues. This study suggests an optimal method of gene delivery to the UtAs of a small rodent for preclinical studies.
McIntireDDBloomSLCaseyBMLevenoKJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med. 1999;340(16):1234–1238.
2.
DoctorBAO’RiordanMAKirchnerHLShahDHackM. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol. 2001;185(3):652–659.
3.
JarvisSGlinianaiaSVTorrioliMG. Cerebral palsy and intrauterine growth in single births: European collaborative study. Lancet. 2003;362(9390):1106–1111.
4.
BlairEStanleyF. Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age. Am J Obstet Gynecol. 1990;162(1):229–237.
5.
ThorntonJGHornbuckleJVailASpiegelhalterDJLeveneM; GRIT study group. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet. 2004;364(9433):513–520.
DavidALTorondelBZacharyI. Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep. Gene Ther. 2008;15(19):1344–1350.
8.
MehtaVAbi-NaderKNPeeblesDM. Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A(165) in the uterine arteries of pregnant sheep. Gene Ther. 2012;19(9):925–935.
CarterAMEndersACJonesCJ. Comparative placentation and animal models: patterns of trophoblast invasion—a workshop report. Placenta. 2006;27(suppl A):S30–S33.
11.
MessA. The Guinea pig placenta: model of placental growth dynamics. Placenta. 2007;28(8-9):812–815.
12.
CarterAM. Animal models of human placentation—a review. Placenta. 2007;28(suppl A):S41–S47.
13.
RobertsCTSohlstromAKindKL. Maternal food restriction reduces the exchange surface area and increases the barrier thickness of the placenta in the guinea pig. Placenta. 2001;22(2-3):177–185.
14.
ByunJHeardJMHuhJE. Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector. J Mol Cell Cardiol. 2001;33(2):295–305.
15.
WangDHeveyMJuompanLY. Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges. Virology. 2006;353(2):324–332.
16.
ChenWLiuMJiaoY. Adenovirus-mediated RNA interference against foot-and-mouth disease virus infection both in vitro and in vivo. J Virol. 2006;80(7):3559–3566.
17.
SantangeloKSBakerSANuovoGDyceJBartlettJSBertoneAL. Detectable reporter gene expression following transduction of adenovirus and adeno-associated virus serotype 2 vectors within full-thickness osteoarthritic and unaffected canine cartilage in vitro and unaffected guinea pig cartilage in vivo. J Orthop Res. 2010;28(2):149–155.
18.
KapoorNLiangWMarbanEChoHC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol. 2013;31(1):54–62.
19.
Li DuanMBordetTMezzinaMKahnAUlfendahlM. Adenoviral and adeno-associated viral vector mediated gene transfer in the guinea pig cochlea. Neuroreport. 2002;13(10):1295–1299.
20.
SenooMMatsubaraYFujiiK. Adenovirus-mediated in utero gene transfer in mice and guinea pigs: tissue distribution of recombinant adenovirus determined by quantitative TaqMan-polymerase chain reaction assay. Mol Genet Metab. 2000;69(4):269–276.
21.
IaccarinoGSmithwickLALefkowitzRJKochWJ. Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis. Proc Natl Acad Sci U S A. 1999;96(7):3945–3950.
22.
KhuranaRZhuangZBhardwajS. Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation. 2004;110(16):2436–2443.
23.
MallawaarachchiCMWeissbergPLSiowRC. Smad7 gene transfer attenuates adventitial cell migration and vascular remodeling after balloon injury. Arterioscler Thromb Vasc Biol. 2005;25(7):1383–1387.
24.
FeldmanLJPastoreCJAubaillyN. Improved efficiency of arterial gene transfer by use of poloxamer 407 as a vehicle for adenoviral vectors. Gene Ther. 1997;4(3):189–198.
25.
XingABoileauPCauzacMChallierJCGirardJHauguel-de MouzonS. Comparative in vivo approaches for selective adenovirus-mediated gene delivery to the placenta. Human Gene Ther. 2000;11(1):167–177.
26.
BlonderJMBairdLFulfsJCRosenthalGJ. Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel. Life Sci. 1999;65(21):PL261–PL266.
27.
El-KamelAH. In vitro and in vivo evaluation of pluronic F127-based ocular delivery system for timolol maleate. Int J Pharm. 2002;241(1):47–55.
28.
BarichelloJMMorishitaMTakayamaKNagaiT. Absorption of insulin from pluronic F-127 gels following subcutaneous administration in rats. Int J Pharm. 1999;184(2):189–198.
29.
KhuranaRMartinJFZacharyI. Gene therapy for cardiovascular disease: a case for cautious optimism. Hypertension. 2001;38(5):1210–1216.
30.
AkashMSRehmanKChenS. Pluronic F127-based thermosensitive gels for delivery of therapeutic proteins and peptides. Polymer Rev. 2014;54(4):573–597.
31.
BatrakovaEVLiSLiYAlakhovVYElmquistWFKabanovAV. Distribution kinetics of a micelle-forming block copolymer pluronic P85. J Control Release. 2004;100(3):389–397.
32.
EgundNCarterAM. Uterine and placental circulation in the guinea-pig: an angiographic study. J Reprod Fertil. 1974;40(2):401–410.
33.
AlemanyRCurielDT. CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors. Gene Ther. 2001;8(17):1347–1353.
34.
EinfeldDASchroederRRoelvinkPW. Reducing the native tropism of adenovirus vectors requires removal of both CAR and integrin interactions. J Virol. 2001;75(23):11284–11291.
35.
Kass-EislerAFalck-PedersenEElfenbeinDHAlviraMButtrickPMLeinwandLA. The impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene transfer. Gene Ther. 1994;1(6):395–402.
36.
LeissnerPLegrandVSchlesingerY. Influence of adenoviral fiber mutations on viral encapsidation, infectivity and in vivo tropism. Gene Ther. 2001;8(1):49–57.
DelotteJNovellasSKohCBongainAChevallierP. Obstetrical prognosis and pregnancy outcome following pelvic arterial embolisation for post-partum hemorrhage. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):129–132.
39.
MehtaVAbi-NaderKNShangarisP. Local over-expression of VEGF-DΔNΔC in the uterine arteries of pregnant sheep results in long-term changes in uterine artery contractility and angiogenesis. PloS One. 2014;9(6):e100021.
40.
HeikkilaAHiltunenMOTurunenMP. Angiographically guided utero-placental gene transfer in rabbits with adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine complexes. Gene Ther. 2001;8(10):784–788.
