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(Investigative Ophthalmology and Visual Science. 2003;44:4497-4504.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0052
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Retinal Neuroprotection against Ischemic Injury Mediated by Intraocular Gene Transfer of Pigment Epithelium-Derived Factor

Hiroyasu Takita,1 Shin Yoneya,1 Peter L. Gehlbach,2 Elia J. Duh,2 Lisa L. Wei,3 and Keisuke Mori1

1From the Department of Ophthalmology, Saitama Medical School, Saitama, Japan; the 2Department of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland; and 3GenVec, Gaithersburg, Maryland.

PURPOSE. To determine whether intraocular gene transfer of pigment epithelium-derived factor (PEDF) protects the retina from ischemia-reperfusion injury.

METHODS. Four days before induction of pressure-induced ischemia, Lewis rats received intravitreous injection of 3 x 109 particles of an adenovirus vector expressing PEDF (AdPEDF.11) in one eye and 3 x 109 particles of an empty adenovirus vector (AdNull.11) in the contralateral eye. Seven days after reperfusion, eyes were enucleated and processed for morphometric analysis. Apoptotic cells stained by TdT-dUTP terminal nick-end labeling (TUNEL) in the retina were counted 12 hours after initiation of reperfusion. Retina levels of PEDF were measured by enzyme-linked immunosorbent assay.

RESULTS. PEDF levels in retinal homogenates from eyes receiving AdPEDF.11 injection were well above the background levels in the untreated baseline and control eyes (P = 0.04). Retinal thickness was preserved in AdPEDF.11-treated eyes. Retinal cell density was significantly greater in the ganglion cell layer (GCL; P = 0.014), inner nuclear layer (INL; P = 0.008), and outer nuclear layer (ONL; P = 0.008) of AdPEDF.11-treated eyes compared with the corresponding layers in AdNull.11-treated eyes. AdNull.11-treated eyes also had significantly more TUNEL-positive cells in these layers than AdPEDF.11-treated eyes (P < 0.05).

CONCLUSIONS. Adenoviral vector-mediated intraocular expression of PEDF significantly increases cell survival after ischemia-reperfusion injury of the retina. The protective effect may result from inhibition of ischemia-induced apoptosis. This study provides proof of concept for a gene transfer approach directed at interrupting programmed cell death induced by retinal ischemic insult.




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