Modulation of in utero total body irradiation induced newborn mouse growth retardation by maternal manganese superoxide dismutase-plasmid liposome (MnSOD-PL) gene therapy

Abstract

To determine the effects of Manganese superoxide dismutase (MnSOD) plasmid liposome (PL) maternal radioprotection on fetal mice, timed pregnant female mice (E14 gestation) were irradiated to 3.0 Gy total body irradiation (TBI) dose, and the number, weight, and growth and development over 6 months after birth of newborn mice was quantitated compared to irradiated controls. Maternal MnSOD-PL treatment at E13 improved pup survival at birth (5.4 ± 0.9/litter compared to irradiated 3.0 Gy controls 4.9 ± 1.1. There was no statistically significant difference in newborn abnormalities, male to female ratio in newborn litters, or other evidence of teratogenesis in surviving newborn mice from MnSOD-PL treated compared to irradiated controls. However, E13 3Gy irradiated pups from gene therapy treated mothers showed a significant increase in both growth and overall survival over 6 months after birth (p = 0.0022).To determine if transgene product crossed the placenta pregnant E13 mice were injected I.V. with hemagglutinin-epitope-tagged MnSOD (100 μgm plasmid in 100 μl liposomes), then 24 hours later fetal mice, placentas, and maternal tissues were removed and tested by both immunohistochemistry and RTPCR for transgene and product. There was no evidence of transgene or product in placenta or any fetal tissue while maternal liver was positive by both assays. The data provide evidence for fetal radioprotection by maternal MnSOD-PL gene therapy before irradiation which is mediated by an indirect bystander effect and is associated with a significant improvement in both survival at birth and growth and development of newborn mice.