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Sina Khalili, Yulia Shifrin, Jingyi Pan, Jaques Belik, Kamiar Mireskandari; The effect of a single anti-VEGF injection on growth and organ development of the neonatal rat. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5544.
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© ARVO (1962-2015); The Authors (2016-present)
Conventional laser treatment for Retinopathy of Prematurity results in loss of peripheral retina and visual field, and may not stop disease progression. Anti-vascular endothelial growth factor (VEGF) treatment is emerging as a promising treatment modality, but there is insufficient evidence on their safety for preterm neonates. We investigate the effect of high dose systemic anti-VEGF in rat pups with equivalent maturity to a 32 week neonate to assess body and organ development.
A single dose of either anti-VEGF antibody, AF-564 (30 µg/kg; R&D systems;n=7), or saline (control group;n=6) was administered to newborn rats intra-peritoneally on the first day of life and their body weight and health was monitored daily. 14 days post treatment, the brain, lung, heart, kidney and liver of the animals were harvested and weighed. The presence of anti-VEGF antibody in the serum was detected using Dot blot analysis. The heart was processed to measure the Fulton index (right ventricular assessment as a surrogate for pulmonary hypertension). All other organs were processed for mRNA expression of VEGF and VEGF receptors (R1&R2) by qPCR.
All pups survived for 14 days post injection and no group differences in body, brain, lung, kidney and liver weights were noted and the VEGF antibody was still detected in serum. The treated pups exhibited increased total heart weight (194.9±6.2 mg versus 156±6.8 mg in control; p=0.0071) and elevated Fulton index (0.346±0.008 versus 0.324±0.003 in control; p<0.0119). AF-564 exposure resulted in increased VEGF mRNA expressions in lung (3.96±0.6 versus 1.22±0.28 in control; p=0.0015) and kidney (3.224±0.59 versus 1.014±0.09 in control; p=0.0109). AF-564 treatment also resulted in increased lung expression of VEGF-R1 mRNA (2.74±0.2 versus 1.49±0.28 in control, p=0.013), and kidney expression of VEGF-R2 mRNA (3.47±0.19 versus 1.004±0.168 in control; p=0.001). No changes were seen in the liver and brain (p=0.95 and p=0.83 respectively for VEGF mRNA expression).
High dose Anti-VEGF antibody exposure in newborn rats did not affect mortality, total body and organ weights, but was associated with pulmonary hypertension. Expression of lung and kidney VEGF and its receptors were increased, whilst the brain and liver did not show changes. Dosing experiments can now be targeted to assess safety threshold and at anti-VEGF dose used in human ROP treatment.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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