期刊
GENE THERAPY
卷 22, 期 5, 页码 365-373出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2015.12
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资金
- Vanderbilt Institute of Chemical Biology
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Research to Prevent Blindness Career Development Award
- Research to Prevent Blindness Unrestricted Funds
- CTSA award from the National Center for Advancing Translational Sciences [UL1TR000445]
- Department of Defense [W81XW-10-1-0528, P30-EY008126, NEI EY022349]
- Fight for Sight
Erythropoietin (EPO) is critical for red blood cell production and is also an effective neuroprotective agent. However, it may contribute to pathological angiogenesis. Here we investigate the angiogenic potential of EPO and a mutant form with attenuated erythropoietic activity, EPO-R76E, on primary human retinal microvascular endothelial cells (HRMECs) and in the adult retina. Assays of death, proliferation and tube formation were performed on HRMECs exposed to EPO, EPO-R76E or media alone. Postnatal day-9 wild-type mice were injected intramuscularly with adeno-associated virus vectors expressing either enhanced green fluorescent protein or EpoR76E. At 3 months, levels of EPO-R76E in the eye were quantified, and the health of the retinal vasculature was assessed by fluorescein angiography and isolectin immunolabeling. Immunohistochemistry, histology and electroretinogram (ERG) assessments were performed as measures of retinal health. Neither EPO nor EPO-R76E induced proliferation or tube formation in HRMECs under the conditions used. EPO-R76E decreased HRMEC death in a dose-dependent manner. Long-term systemic gene delivery of EPO-R76E was safe in terms of retinal vasculature, histology and the ERG in vivo. Our results show that EPO-R76E can block HRMEC death, consistent with its role in erythropoiesis and neuroprotection. In addition, long-term gene delivery of EPO-R76E is safe in the adult retina.
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