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K. Jaworski, C. Wraight, G. Tachas, S. Lofthouse, J. Wilkinson–Berka; An Antisense Oligonucleotide Targeting the Growth Hormone Receptor Inhibits Neovascularization in a Mouse Model of Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3225.
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© ARVO (1962-2015); The Authors (2016-present)
Neovascularization is a hallmark feature of diabetic retinopathy and age–related macular degeneration. New therapies are in development that target some of the factors known to be involved such as VEGF and IGF–I. We have previously demonstrated that a 2'–O–methoxyethyl modified antisense oligonucleotide targeted to the mouse growth hormone (GH) receptor inhibits GH binding and reduces serum IGF–I levels in normal mice.
To determine whether a systemically delivered antisense oligonucleotide targeted to the GH receptor could inhibit neovascularization in a mouse model of retinopathy of prematurity (ROP).
Retinopathy was induced by housing mice across days P7 to P12 in a hyperoxic chamber (75% O2) followed by 5 days in room air. Sham mice were housed in room air from birth until P17. ROP and sham mice were administered GH receptor antisense, the somatostatin analogue, octreotide, or control oligonucleotides. Agents were administered by either early intervention (7 total doses, day P7, 8, 9, 11, 13, 15 and 17) or late intervention (5 daily doses from day P12 to P16). Neovascularization was assessed at day 17 by counting blood vessel profiles in the inner retina from at least 4 randomly chosen paraffin sections per eye.
In ROP mice treated with vehicle (saline), neovascularization was 2.5–fold higher than sham groups. Neovascularization was decreased in ROP mice treated with 5, 10, 20 or 30mg/kg of GH receptor antisense, administered intraperitoneally by late intervention. Early interventon with GH receptor antisense at 5 and 30mg/kg also reduced neovascularization. The 30mg/kg early intervention group exhibited the greatest anti–angiogenic response and was 38% lower than ROP+vehicle. This compared to a 26% inhibition in the ROP+octreotide group. Two control oligonucleotides with the same chemical structure did not inhibit neovascularization in either the early or late intervention models at 20mg/kg. However one of the control oligonucleotides did show a small (18%) reduction compared to ROP+vehicle when dosed at 30mg/kg. There was nevertheless a significant reduction in neovascularization in the corresponding 30mg/kg antisense–treated group compared to this oligonucleotide control group, indicating a clear sequence specific effect.
Systemically delivered antisense oligonucleotides directed against the GH receptor are a potential novel therapy for neovascularization related disorders.
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