An antisense oligonucleotide targeting the growth hormone receptor inhibits neovascularization in a mouse model of retinopathy.
OBJECTIVE
We have demonstrated that a 2'-O-methoxyethyl modified antisense oligonucleotide against the mouse growth hormone (GH) receptor (GHr) reduces GH binding and serum insulin-like growth factor-1 in normal mice. We tested whether this systemically delivered antisense oligonucleotide could inhibit neovascularization in mice with oxygen induced retinopathy (OIR).


METHODS
OIR was induced in C57BL/6 mice by housing them in 75% oxygen across postnatal days (P)7 to 12 followed by five days in room air. Shams were in room air from P0-17. GHr antisense oligonucleotide, ATL 227446, was administered by early (P7, 8, 9, 11, 13, 15, and 17) or late (P12-16) intervention at doses of 5, 10, 20, and 30 mg/kg. Other mice were treated with either vehicle (saline), the somatostatin analog octreotide (20 mg/kg/bi-daily), or control oligonucleotides ATL 261303 (at 20 mg/kg by late and early intervention) or ATL 260120 (at 20 and 30 mg/kg by early intervention only). Blood vessel profiles were counted in 3 mm paraffin sections of inner retina.


RESULTS
OIR increased blood vessel profiles by 2.5 fold compared to shams. In OIR, early intervention GHr antisense oligonucleotide ATL 227446 reduced blood vessel profiles at higher doses including 10 mg/kg, and 30 mg/kg resulted in the greatest reduction (38%). In OIR, late intervention with all doses of GHr antisense oligonucleotide ATL 227446 reduced blood vessel profiles to a similar extent, and the highest dose resulted in a 26% reduction compared to OIR. Octreotide reduced blood vessel profiles in OIR mice by 26%. In OIR, ATL 261303 had no effect on blood vessel profiles, while 30 mg/kg ATL 260120 reduced blood vessel profiles by 18%.


CONCLUSIONS
Systemically delivered antisense oligonucleotides directed against the GHr are a potential novel treatment for ocular neovascularization related disorders.
Wilkinson-Berka
Jennifer L
JL
Department of Immunology, Monash University, Alfred and Medical Research Precinct, Melbourne, Victoria, Australia. Jennifer.Wilkinson-Berka@med.monash.edu.au
Lofthouse
Shari
S
Jaworski
Kassie
K
Ninkovic
Slavisa
S
Tachas
George
G
Wraight
Christopher J
CJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015282:Octreotide / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010100:Oxygen; D011986:Receptors, Somatotropin / Q000235:genetics*; D012164:Retinal Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology
D016376:Oligonucleotides, Antisense; D011986:Receptors, Somatotropin; D015282:Octreotide; D010100:Oxygen