Safety and angiogenic effects of systemic gene delivery of a modified erythropoietin
| Autor: | Wesley S. Bond, Tonia S. Rex, A M de Lucas Cerrillo |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
retina
Pathology medicine.medical_specialty Mutation Missense Neovascularization Physiologic CHO Cells Gene delivery Biology Pharmacology Article Neovascularization Mice angiogenesis chemistry.chemical_compound Cricetulus Cricetinae hemic and lymphatic diseases Genetics medicine Animals Humans Erythropoiesis primary human retinal microvascular endothelial cells Molecular Biology Cells Cultured Tube formation Retina medicine.diagnostic_test Gene Transfer Techniques Retinal Vessels Retinal Fluorescein angiography 3. Good health Mice Inbred C57BL medicine.anatomical_structure chemistry Erythropoietin Molecular Medicine Endothelium Vascular erythropoietin medicine.symptom medicine.drug |
| Zdroj: | Gene therapy |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2015.12 |
| Popis: | Erythropoietin (EPO) is critical for red blood cell production and is also an effective neuroprotective agent. However, it may also 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 (HRMEC) 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 assessments were performed as measures of retinal health. Neither EPO nor EPO-R76E induced proliferation or tube-formation in HRMEC 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 electroretinogram 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. |
| Databáze: | OpenAIRE |
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