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Susanna S. Park, Sergio Caballero, Gerhard Bauer, Bradley Shibata, Alan Roth, Paul G. Fitzgerald, Krisztina I. Forward, Ping Zhou, Jeannine McGee, David G. Telander, Maria B. Grant, Jan A. Nolta; Long-Term Effects of Intravitreal Injection of GMP-Grade Bone-Marrow–Derived CD34+ Cells in NOD-SCID Mice with Acute Ischemia-Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(2):986-994. doi: 10.1167/iovs.11-8833.
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To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)–grade human bone-marrow–derived CD34+ cells in NOD-SCID (nonobese diabetic–severe combined immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy.
Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 × 104 CD34+ cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning.
Immunohistochemical staining 4 months after injection showed detectable CD34+ cells in the retinal vasculature. ERG at 8 months after CD34+ cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34+ cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells.
Intravitreal administration of GMP-grade human bone-marrow–derived CD34+ cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy.
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