June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
AAV-Mediated Neurotrophin-4 Is Neuroprotective In Murine Model Of Microbead-Induced Glaucoma with Neurotrophin Expression in the Visual Pathway
Author Affiliations & Notes
  • Anna Demetriades
    Glaucoma Research Laboratory, Weill Cornell Medical College, New York, NY
  • Lihua Guo
    Glaucoma Research Laboratory, Weill Cornell Medical College, New York, NY
  • Chendong Pan
    Glaucoma Research Laboratory, Weill Cornell Medical College, New York, NY
  • Footnotes
    Commercial Relationships Anna Demetriades, None; Lihua Guo, None; Chendong Pan, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4940. doi:
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      Anna Demetriades, Lihua Guo, Chendong Pan; AAV-Mediated Neurotrophin-4 Is Neuroprotective In Murine Model Of Microbead-Induced Glaucoma with Neurotrophin Expression in the Visual Pathway. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4940.

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

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Abstract

Purpose: To determine if an adeno-associated viral (AAV2) vector with a CAG promoter expressing neurotrophin-4 (NT4) is neuroprotective in the murine model of microbead-induced ocular hypertension and the extent to which NT4 is expressed in the visual pathway.

Methods: Polystyrene microbeads were injected into the anterior chamber of adult mice to elevate intraocular pressure (IOP). An intravitreal injection containing 1x10e9 vector genomes of either AAV.NT4.HA or AAV.Null was administered into the same eye. Intraocular pressure was measured by TonoLab tonometry at weekly intervals. Mice were sacrificed at four weeks and retinal ganglion cell (RGC) loss was quantified. Enzyme-linked immunosorbent assay (ELISA) and HA immunohistochemistry was performed to determine NT4 expression in the visual pathway.

Results: Increased IOP was confirmed in microbead-injected eyes by tonometer. Uninjected control eyes had a mean RGC count of 3065±410 cells/mm2 (n=15). At four weeks, microbead-injected eyes that received AAV.NT4.HA demonstrated 2141±85 cells/mm2 (n=8) and microbead-injected eyes that received AAV.Null demonstrated 1547±89 cells/mm2 (n=10). Thus, microbead- injected eyes treated with AAV.NT4.HA contained over 135% increase in viable RGCs at four weeks compared to eyes treated with AAV.Null (p<0.005). Compared to uninjected mice (n=5), intravitreous AAV.NT4.HA resulted in increased NT4 levels (ng NT4/mg total protein) in the retina (3.7 vs. 0.002), optic nerve (19.8 vs. 0.04), lateral geniculate nucleus (0.1 vs. 0.002) and superior colliculus (0.1 vs. 0.004). There was no increase in NT4 levels in the visual cortex. HA immunohistochemistry confirmed NT4 expression in RGCs, lateral geniculate nucleus and superior colliculus but not in the visual cortex.

Conclusions: Intravitreal AAV.NT4 results in NT4 expression from RGCs to their synapses in the lateral geniculate nucleus and superior colliculus and has neuroprotective effects on RGC survival. Increased NT4 expression has no effect on IOP, which is consistent with NT4-induced neuroprotection in an environment of elevated IOP. Intravitreal AAV.NT4 may represent a promising treatment for glaucoma targeting the neurodegenerative aspect of this disease.

Keywords: 615 neuroprotection • 531 ganglion cells • 449 cell survival  
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