June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Preprogrammed Hematopoietic Stem Cells as a Systemic Therapy for Dry AMD
Author Affiliations & Notes
  • Maria Grant
    Pharmacology and Therapeutics, University of Florida, Gainesville, FL
  • Xiaoping Qi
    Anatomy and Cell Biology, University of Florida, Gainesville, FL
  • Yuanqing Yan
    Pharmacology and Therapeutics, University of Florida, Gainesville, FL
  • Lynn Shaw
    Pharmacology and Therapeutics, University of Florida, Gainesville, FL
  • Alfred Lewin
    Molecular Genetics and Microbiology, University of Florida, Gainesville, FL
  • Michael Boulton
    Anatomy and Cell Biology, University of Florida, Gainesville, FL
  • Footnotes
    Commercial Relationships Maria Grant, None; Xiaoping Qi, None; Yuanqing Yan, None; Lynn Shaw, None; Alfred Lewin, University of Florida (P); Michael Boulton, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 3281. doi:https://doi.org/
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      Maria Grant, Xiaoping Qi, Yuanqing Yan, Lynn Shaw, Alfred Lewin, Michael Boulton; Preprogrammed Hematopoietic Stem Cells as a Systemic Therapy for Dry AMD. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3281. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Dry AMD represents 85% of AMD and is associated with retinal pigment epithelial (RPE) dysfunction and cell death for which there is no treatment. Previously we showed that systemic delivery of genetically reprogrammed hematopoietic stem cells (HSC) with the RPE differentiation marker, RPE 65, enhances repair of the RPE layer and results in recovery of visual function (VF) in the sodium iodate model of acute RPE cell loss (Sengupta et al 2009). In this study, we tested the efficacy of programming HSC in the superoxide dismutase 2 knockdown (SOD2 KD) model for dry AMD which generates a defect predominantly in the RPE.

Methods: SOD2 KD was achieved by subretinal injection of AAV containing an SOD2 ribozyme under the direction of an RPE specific promoter (VMD2). Systemic administration of HSC infected with lentivirus expressing human RPE 65 (LV hRPE65) or infected with lentivirus expressing LacZ (LV LacZ) was undertaken at 1, 3 and 6 months post induction of the AMD phenotype with SOD2 KD. ERGs and optomotor response tests were used to assess VF. Donor RPE65-HSC integration was assessed by confocal immunofluorescence microscopy. Histology and immunohistochemistry (IH) were used to identify retinal histology and RPE repair.

Results: LV gave a 75.5±5.5% (p<0.01) efficient transfection of HSC and RPE65 expression was confirmed by IH. Systemic administration of LV hRPE65 programmed mouse HSCs maintained VF, retained retinal thickness and prevented degeneration of the retina of SOD2 KD mice. This preservation was not observed by null or LV LacZ programmed HSC. At 1, 3 and 6 months following HSC injections, photopic and scotopic ERGs were significantly higher only in SOD2 KD mice administered LV hRPE65-mHSC but not mice receiving LV LacZ-mHSC, untreated HSCs or untreated SOD2 KD mice. Using optomotor responses to further assess VF, at 1 month post SOD KD, mice injected with LV RPE65-mHSC retained VF to a level similar to WT mice, VF declined slightly(<20%) at the 6-month time point.

Conclusions: Introduction of RPE-65 programmed HSC maintained VF, retained retinal thickness and prevented degeneration. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential for prevention, rather than intervention in early AMD and other RPE based diseases.

Keywords: 412 age-related macular degeneration • 721 stem cells • 701 retinal pigment epithelium  
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