April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Systemic rAAV Delivery of Modified Erythropoietin is Neuroprotective in a Mouse Model of Induced Ocular Hypertension
Author Affiliations & Notes
  • Wesley S Bond
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • Ana Maria de Lucas-Cerrillo
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • D'Anne S Duncan
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • YPaul Chang
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • Rebecca M Sappington
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • Tonia S Rex
    Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, TN
  • Footnotes
    Commercial Relationships Wesley Bond, None; Ana de Lucas-Cerrillo, None; D'Anne Duncan, None; YPaul Chang, None; Rebecca Sappington, None; Tonia Rex, PCT/US2012/021247 (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2428. doi:https://doi.org/
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      Wesley S Bond, Ana Maria de Lucas-Cerrillo, D'Anne S Duncan, YPaul Chang, Rebecca M Sappington, Tonia S Rex; Systemic rAAV Delivery of Modified Erythropoietin is Neuroprotective in a Mouse Model of Induced Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2428. doi: https://doi.org/.

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

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Abstract

Purpose: Our goal is to investigate the neuroprotective effects of systemic recombinant adeno-associated virus (rAAV) gene delivery of forms of erythropoietin (Epo) that have attenuated erythropoietic activity to provide long-term, sustained treatment in an induced mouse model of glaucoma.

Methods: C57BL/6 mice were injected intramuscularly with 10^9 vgc rAAV2/8 delivering eGFP or Epo mutants R76E, R76E+S100E, or R76E+R103E. To induce ocular hypertension, anterior chambers were injected with 15-µm diameter microbeads or saline 1 month after rAAV administration. Elevation of intraocular pressure (IOP) was verified by tonometry. Baseline and endpoint visual function was assessed by flash visually evoked potential (fVEP) immediately prior and 1 month following induction. At 1 month post-induction, tissue was collected, and retinal ganglion cell (RGC) axons were evaluated by optic nerve histology and fluorescent cholera toxin B anterograde transport. Blood hematocrit was also assessed at collection.

Results: Hematocrit was significantly elevated (86%) in mice treated with rAAV.EpoR76E but not elevated in mice treated with rAAV.EpoR76E+S100E (44%) or rAAV.EpoR76E+R103E (44%). Mean IOP of 18.7±2.8 mmHg was observed in microbead-injected eyes 1 week post-induction compared to 14.4±0.9 mmHg in saline controls. At 1 month post-induction, microbead-injected rAAV.eGFP controls developed 60% reduction in endpoint fVEP P1 amplitude from baseline, 30% reduction in RGC axon density, and impairment of RGC anterograde transport. Microbead-injected mice treated with rAAV.EpoR76E showed no significant decrease in endpoint fVEP P1 amplitude from baseline. RGC axon density in microbead-injected mice treated with rAAV.EpoR76E+S100E and rAAV.EpoR76E+R103E improved 25% and 20%, respectively, compared to rAAV.eGFP-treated mice. Microbead-injected mice treated with rAAV.EpoR76E showed improvement in RGC anterograde transport compared to rAAV.eGFP controls.

Conclusions: Gene delivery of non-hematopoietic modified Epo appears to attenuate glaucomatous changes in the induced model of ocular hypertension, indicating that neuroprotection by Epo is not specific to the DBA/2J model of glaucoma.

Keywords: 538 gene transfer/gene therapy • 615 neuroprotection • 568 intraocular pressure  
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