July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Promising New Gene Therapy for Optic Nerve Regeneration and Neuroprotection
Author Affiliations & Notes
  • Margaret McDougal Runner
    Ophthalmology, University of Southern California, Los Angeles, California, United States
  • Claire-Anne Gutekunst
    Neurosurgery, Emory University, ATLANTA, Georgia, United States
  • Robert Gross
    Neurosurgery, Emory University, ATLANTA, Georgia, United States
  • Footnotes
    Commercial Relationships   Margaret Runner, None; Claire-Anne Gutekunst, None; Robert Gross, None
  • Footnotes
    Support  NIH Grant 1R03NS091699-01, Emory University Research Commitee grant, Neurosurgery Research and Education Foundation Medical Student Summer Research Fellowship award
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2251. doi:
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      Margaret McDougal Runner, Claire-Anne Gutekunst, Robert Gross; Promising New Gene Therapy for Optic Nerve Regeneration and Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2251.

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

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Purpose : The Rho/ROCK inhibitor, C3 transferase (C3), is a promising new treatment for glaucoma and traumatic optic nerve damage. In addition to lowering intraocular pressure (IOP), C3 protects and regenerates retinal ganglion cells (RGCs) after injury. However, these effects are limited by C3’s short duration of action and poor distribution. To address this, adeno-associated viral (AAV) vectors tagged with green fluorescent protein (GFP) were engineered to express intracellular C3 (icC3) and a secretable/permeable (sp) truncated C3 (C3t) to allow for long-term and widespread RhoA inhibition.

Methods : C3 gene therapy was delivered via intravitreous injection in the rat optic nerve crush (ONC) model, and animals were sacrificed at 4 and 8 weeks. RGC survival was quantified following immunostaining of the retina with an RGC-specific antibody. Optic nerves were labeled with anterograde tracer and underwent tissue clearance to allow detailed visualization of regenerating axons through the whole nerve.

Results : In the control group, only 5% of RGCs survived 8 weeks after injury, whereas treatment with AAV-icC3GFP protected 45% of RGCs, and the widespread distribution by AAV-spGFPtC3 kept a remarkable 76% of RGCs alive. Robust long-distance axon regeneration was observed at 4 weeks in both treatment groups compared to controls, with a significant 38- and 24-fold increase in axon regeneration at 1 mm past the crush site for AAV-icC3GFP (p = 0.005) and AAV-spGFPtC3 (p = 0.02), respectively.

Conclusions : Modified C3 gene therapy greatly enhances RGC survival and axon regeneration after injury. These data, along with the known IOP lowering effects, suggest C3 gene therapy as an effective neuroprotective and regenerative treatment for glaucoma or traumatic damage to the optic nerve.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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