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Updated: Jun 2, 2026
Limbal Approach-Subretinal Injection of Viral Vectors for Gene Therapy in Mice Retinal Pigment Epithelium
Published on: August 7, 2015
Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J
Timothy A Sullivan1, Eldon E Geisert, Jessica Hines-Beard
1Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Abstract:
A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.
Insights
A novel mutant erythropoietin (EPO) derivative, EpoR76E, protects neurons in a glaucoma model without causing dangerous polycythemia. This gene therapy preserves vision and optic nerve function, offering hope for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Ophthalmology
- Genetics
Background:
- Neurodegenerative diseases, like glaucoma, involve progressive neuron loss.
- Erythropoietin (EPO) shows neuroprotection but causes polycythemia.
- A mutant EPO (EpoR76E) was engineered to be neuroprotective without erythropoietic effects.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of EpoR76E gene therapy in a mouse model of glaucoma.
- To determine if EpoR76E prevents polycythemia while protecting retinal ganglion cells and optic nerve axons.
Main Methods:
- A single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E).
- Assessment of retinal ganglion cell survival, axonal integrity, and hematocrit levels.
- Evaluation of visual function using flash visual evoked potentials.
Main Results:
- Systemic EpoR76E treatment protected retinal ganglion cell bodies and optic nerve axons.
- Hematocrit levels remained within normal limits, indicating no polycythemia.
- Preserved retinal ganglion cells retained visual function, as shown by electrophysiological recordings.
Conclusions:
- EpoR76E gene therapy offers a potential treatment for glaucoma, protecting neurons and vision without adverse effects.
- This approach represents a novel therapeutic strategy for neurodegenerative conditions.
- EpoR76E's broad cellular targets suggest potential applications in other neurodegenerative diseases.
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