Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction.
Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal-fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta-specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical translation of this novel therapy.
1 Center for Molecular Fetal Therapy, Division of Pediatric, General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine , Cincinnati, OH 45229-3039.
Sundeep G
SG
Keswani
Swathi
S
Balaji
Anna B
AB
Katz
Alice
A
King
Khaled
K
Omar
Mounira
M
Habli
Charles
C
Klanke
Timothy M
TM
Crombleholme
D000256:Adenoviridae; D000818:Animals; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000628:therapy*; D005333:Fetus / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000254:growth & development; D008168:Lung / Q000187:drug effects / Q000254:growth & development; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D010927:Placental Insufficiency / Q000235:genetics*; D011247:Pregnancy; D011817:Rabbits
D007334:Insulin-Like Growth Factor I