September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP.
Author Affiliations & Notes
  • Tailoi Chan-Ling
    Retinal & Developmental Neurobiology Laboratory, University of Sydney, Sydney, New South Wales, Australia
  • Nigel L Barnett
    Queensland Eye Institute, Brisbane, Queensland, Australia
  • Rita Maccarone
    University of L'Aquila, L'Aquila, Italy
  • Jan Provis
    John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
  • Mark Koina
    ACT Pathology, Canberra, Australian Capital Territory, Australia
    Retinal & Developmental Neurobiology Laboratory, University of Sydney, Sydney, New South Wales, Australia
  • Ping Hu
    Retinal & Developmental Neurobiology Laboratory, University of Sydney, Sydney, New South Wales, Australia
  • Riccardo Natoli
    John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
  • Silvia Bisti
    University of L'Aquila, L'Aquila, Italy
  • Robert A Linsenmeier
    Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, United States
  • Samuel Adamson
    Retinal & Developmental Neurobiology Laboratory, University of Sydney, Sydney, New South Wales, Australia
  • Footnotes
    Commercial Relationships   Tailoi Chan-Ling, None; Nigel Barnett, None; Rita Maccarone, None; Jan Provis, None; Mark Koina, None; Ping Hu, None; Riccardo Natoli, None; Silvia Bisti, None; Robert Linsenmeier, None; Samuel Adamson, None
  • Footnotes
    Support  NHMRC Project Grant 571100, NHMRC Principal Research Fellowship 1005730, Sydney Medical Foundation, Baxter Charitable Foundation, Rebecca L. Cooper Medical Research Foundation, Bonnie Babes Foundation & RG Arnott Foundation (TCL) NWG Macintosh Memorial Fund (SA). We thank Cassie Rayner (QEI) for undertaking P18 & P25 ERG
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Tailoi Chan-Ling, Nigel L Barnett, Rita Maccarone, Jan Provis, Mark Koina, Ping Hu, Riccardo Natoli, Silvia Bisti, Robert A Linsenmeier, Samuel Adamson; Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP.. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The initiating event in ROP is delayed retinal vascularization as a consequence of required oxygen supplementation. We hypothesized neonates in high O2 environments should be reared in total darkness, creating a “metabolic sump” via continuous photoreceptor depolarization, eliminating the initiating event in the disease.

Methods : 4 groups of SD rats were examined at P14 & P18: 1) Room Air + normal light reared (NLR); 2) Room air + dark rearing (DR). 3) 50/10 OIR + normal light 4) 50/10 OIR + dark rearing. Retinae were examined for vascular density index (VDI), vaso-obliteration & neovascularization, hypoxyprobe-1, astrocyte ensheathment, ultrastructure via TEM and gene expression via qPCR. Electroretinograms (ERG) were recorded at P18 & P25 in OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75% inspired O2 in NLR & DR.

Results : Confirming our proof of principle, DR rats had a higher vascular density than NLR rats in room air (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from vaso-obliteration (20.6% ± 4.9 v 39.0% ± 4.0 p<0.05). In the hypoxic 2nd phase of OIR, DR reduced pre-retinal neovascularization (4.1% ± 0.9 v 15.8% ± 1.3 p<0.05); tissue hypoxia as evidenced by reduced HP1; protected astrocytes & pericytes from hypoxic damage; and preserved retinal ultrastructure. DR prevented upregulation of HIF1a (65.5% ± 27.2 v -20.4 ± 4.6 p<0.05), VEGF164 (496.6% ± 11.1 v 291.2% ± 60.1 p<0.05) and AP1/Jun (179.8% ± 26.9 v -51.7 ± 16.7, p<0.05) in peripheral retina at P14. DR had no detrimental effects on retinal function as evidenced by ERG at P18 and P25 in OIR, & after long-term DR. O2 profile modeling under DR at 60% inspired O2 at P14 showed that inner retina maintains 'physiological hypoxia' in DR but not in NLR ,whilst 75% O2 overwhelms the protective effect of DR.

Conclusions : DR precludes the initiation of ROP by maintaining retinal vascularization during the 1st phase of OIR. As a consequence, when neonates are returned to RA, the retina is protected from hypoxia-induced vaso-proliferation in phase 2 of ROP and it’s associated damaging effects on retinal structure and function. This cost-effective, non-invasive intervention by reducing disease severity can supplement current therapies and, may negate the need for invasive therapies including laser and anti-VEGF.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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