Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34 + cells in NOD-SCID mice with acute ischemia-reperfusion injury

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

Research output: Contribution to journalArticle

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Abstract

PURPOSE. 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. METHOD. 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 × 10 4 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. RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish (US)
Pages (from-to)986-994
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

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Severe Combined Immunodeficiency
Intravitreal Injections
Reperfusion Injury
Bone Marrow
Electroretinography
Staining and Labeling
Injections
Cell Separation
Hematoxylin
Eosine Yellowish-(YS)
Intraocular Pressure
Histology
Cell Proliferation
Clinical Trials
Safety

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34 + cells in NOD-SCID mice with acute ischemia-reperfusion injury. / Park, Susanna S.; Caballero, Sergio; Bauer, Gerhard; Shibata, Bradley; Roth, Alan; Fitzgerald, Paul G.; Forward, Krisztina I.; Zhou, Ping; McGee, Jeannine; Telander, David G.; Grant, Maria B.; Nolta, Jan A.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 2, 02.2012, p. 986-994.

Research output: Contribution to journalArticle

Park, SS, Caballero, S, Bauer, G, Shibata, B, Roth, A, Fitzgerald, PG, Forward, KI, Zhou, P, McGee, J, Telander, DG, Grant, MB & Nolta, JA 2012, 'Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34 + cells in NOD-SCID mice with acute ischemia-reperfusion injury', Investigative Ophthalmology and Visual Science, vol. 53, no. 2, pp. 986-994. https://doi.org/10.1167/iovs.11-8833
Park, Susanna S. ; Caballero, Sergio ; Bauer, Gerhard ; Shibata, Bradley ; Roth, Alan ; Fitzgerald, Paul G. ; Forward, Krisztina I. ; Zhou, Ping ; McGee, Jeannine ; Telander, David G. ; Grant, Maria B. ; Nolta, Jan A. / Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34 + cells in NOD-SCID mice with acute ischemia-reperfusion injury. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 2. pp. 986-994.
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abstract = "PURPOSE. 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. METHOD. 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 × 10 4 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. RESULTS. 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. CONCLUSIONS. 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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AU - Caballero, Sergio

AU - Bauer, Gerhard

AU - Shibata, Bradley

AU - Roth, Alan

AU - Fitzgerald, Paul G.

AU - Forward, Krisztina I.

AU - Zhou, Ping

AU - McGee, Jeannine

AU - Telander, David G.

AU - Grant, Maria B.

AU - Nolta, Jan A.

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N2 - PURPOSE. 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. METHOD. 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 × 10 4 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. RESULTS. 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. CONCLUSIONS. 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.

AB - PURPOSE. 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. METHOD. 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 × 10 4 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. RESULTS. 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. CONCLUSIONS. 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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