Modulation of in utero total body irradiation induced newborn mouse growth retardation by maternal manganese superoxide dismutase-plasmid liposome (MnSOD-PL) gene therapy.
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 with irradiated controls. Maternal MnSOD-PL treatment at E13 improved pup survival at birth (5.4±0.9 per litter) compared with non-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 with irradiated controls. However, E14 3 Gy 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 intravenously with hemagglutinin-epitope-tagged MnSOD (100 μg plasmid in 100 μl liposomes), then after 24 h, fetal mice, placentas and maternal tissues were removed and tested by both immunohistochemistry and reverse transcriptase-PCR 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.
Department of Radiation Oncology, UPCI Cancer Institute, Pittsburgh, PA 15232, USA.
M W
MW
Epperly
T
T
Smith
X
X
Zhang
J P
JP
Goff
D
D
Franicola
B
B
Greenberger
P
P
Komanduri
H
H
Wang
J S
JS
Greenberger
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D005260:Female; D005313:Fetal Death / Q000517:prevention & control; D005317:Fetal Growth Retardation / Q000517:prevention & control; D005333:Fetus / Q000528:radiation effects; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D013482:Superoxide Dismutase / Q000235:genetics*; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D008081:Liposomes; D011837:Radiation-Protective Agents; D013482:Superoxide Dismutase
In Vivo. 2003 Jan-Feb;17(1):13-21
12655784
Curr Gene Ther. 2003 Jun;3(3):183-95
12762478
J Clin Invest. 2009 Sep;119(9):2590-600
19652363
Health Phys. 1995 Jun;68(6):766-72
7759254
Biol Blood Marrow Transplant. 2002;8(4):175-87
12014807
Radiat Res. 2003 Mar;159(3):361-70
12600239
Lab Anim (NY). 2009 Sep;38(9):305-10
19701181
Radiat Res. 1998 Sep;150(3):316-29
9728661
Dev Biol. 2008 Oct 15;322(2):302-13
18722365
Biol Blood Marrow Transplant. 1999;5(4):204-14
10465100
In Vivo. 2009 Mar-Apr;23(2):323-36
19414422
J Natl Cancer Inst. 2008 Mar 19;100(6):428-36
18334707
Teratology. 2001 Jul;64(1):45-50
11410910
Teratology. 1999 Mar;59(3):133-8
10194803
Gene Ther. 2000 Jun;7(12):1011-8
10871749
Int J Cancer. 2001 Feb 20;96(1):11-21
11241326
Radiat Oncol Investig. 1999;7(4):204-17
10492161
N Engl J Med. 2009 Apr 16;360(16):1597-605
19369666
Radiat Res. 2008 Sep;170(3):269-74
18763869
Radiat Res. 2001 Dec;156(6):718-23
11741495
Radiat Res. 2004 Apr;161(4):373-9
15038761
Radiat Res. 2001 Jan;155(1 Pt 1):2-14
11121210
Radiat Res. 2000 Oct;154(4):365-74
11023599
Toxicol Appl Pharmacol. 2004 Sep 1;199(2):162-74
15313588
Radiat Res. 2008 Oct;170(4):437-43
19024650
Radiat Res. 1994 Apr;138(1):121-6
8146291
Br J Radiol. 2005 Oct;78(934):928-33
16177016
Radiat Oncol Investig. 1999;7(6):331-42
10644056
Radiat Res. 2002 May;157(5):568-77
11966323
Hum Gene Ther. 2011 Mar;22(3):336-42
20873987
Mutat Res. 2004 Dec 2;568(1):79-87
15530541
Int J Cancer. 2001 Aug 20;96(4):221-31
11474496
Radiat Res. 2007 Jun;167(6):693-702
17523844
Gene Ther. 2003 Jan;10(2):163-71
12571645