December 2018

NEWS & OPINION

Is vision restoration after glaucoma possible?


by Liz Hillman EyeWorld Senior Staff Writer

“My hope is that we can soon come up with a smart clinical study to test the ability of insulin to restore vision in glaucoma, and hopefully move this forward for the benefit of the patients.”
—Adriana Di Polo, PhD

New research suggests topical insulin could restore function of retinal ganglion cells damaged by glaucoma

Glaucoma treatment has focused largely on prevention, stalling progression to preserve vision and stop otherwise permanent damage to the optic nerve. However, new research presents the potential for a restorative therapy.
A paper published in the journal Brain describes how insulin, in the form of an eye drop, led to regeneration of retinal ganglion cells (RGCs) dendrites, which receive information from photoreceptors, and restoration of retinal function.1
Ten years ago, Adriana Di Polo, PhD, professor, Department of Neuroscience, University of Montreal, Quebec, Canada, described working on axonal regeneration in the field of glaucoma and other types of neurodegenerative diseases.
“We know that the axon is an important part of the neuron that is required for neurotransmission, a very important process,” Dr. Di Polo said. “However, almost nothing was known about dendrites, the other side of the neurons, and their ability to regenerate after optic nerve injury. We reasoned that in order to restore the function of retinal ganglion cells and the retinal circuit, both sides of the neuron need to function for the flow of information to go through.
“It started as a scientific question based on curiosity: Can dendrites regenerate?” Dr. Di Polo continued. “After all these years, we finally demonstrated that mammalian neurons do have the ability to regenerate, not only axons under certain circumstances, but also dendrites. Dendrites might be easier to regenerate than axons because at least in the retina, ganglion cell dendrites are closer to the target neurons that they need to make connections with, so it was a nice and neat system to test this question.”
What led Dr. Di Polo and her coinvestigators to test insulin in this regenerative process? Dr. Di Polo cited a study from her laboratory published in 2015 where they identified a key intracellular protein inside neurons known as the mammalian target of rapamycin (mTOR), a kinase that regulates several cellular functions, including growth.2
“We had previously demonstrated that this particular protein, mTOR, was important for the maintenance of dendrites after optic nerve injury,” Dr. Di Polo said.
The team then wondered, in the context of wanting to stimulate regeneration of these cells, what factor could stimulate mTOR and its complexes. It turns out it was insulin. The possibility of insulin playing a role in glaucoma neurodegeneration, in the context of impaired insulin signaling or insulin resistance, has also been suggested.3,4
Dr. Di Polo and her fellow researchers, as described in the recently published paper, tested whether a topical or systemic administration of insulin had a regenerative effect on the dendrites in a mouse model of acute optic nerve transection to selectively damage retinal ganglion cell axons. They used the synthetically manufactured human insulin that is already approved and used by diabetic patients, formulating it as an eye drop for that administration.
After dendritic retraction was observed in the mice, the researchers administered insulin or the control vehicle. “Vehicle-treated retinal ganglion cells displayed shrunken dendritic arbors with considerably fewer branches. In contrast, insulin administration, independently of delivery route, promoted robust retinal ganglion cell dendrite regeneration and restored process length, arbor area and complexity,” Agostinone et al. reported.
In other words, the research demonstrated the robust effect of insulin to regenerate retinal ganglion cell dendritic arbors and restore function in these cells. Electrophysiological assays in the form of an electroretinogram showed strong recovery of light-triggered responses after insulin treatment.
As for side effects to the topically applied insulin, Dr. Di Polo said they did not observe redness, inflammation, or a hypoglycemic effect.
One piece of information that is still missing is whether visual behavior—actual sight—was restored. Dr. Di Polo and her team are currently conducting those experiments. In addition, they are setting up collaborations to test therapies in a non-human primate model of glaucoma, which will be used to inform the design of a clinical trial in humans.
“My hope is that we can soon come up with a smart clinical study to test the ability of insulin to restore vision in glaucoma, and hopefully move this forward for the benefit of the patients,” Dr. Di Polo said. “I am grateful for the funding we received from the Glaucoma Research Foundation to carry out this promising study that might have implications for the treatment of glaucoma.”
Dr. Di Polo also indicated that these findings could have implications for other neurodegenerative diseases with dendritic pathology such as Alzheimer’s and Parkinson’s disease.

References

1. Agostinone J, et al. Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury. Brain. 2018;141:1963–1980.
2. Agostinone J, Di Polo A. Retinal ganglion cell dendrite pathology and synapse loss: implications for glaucoma. Prog Brain Res. 2015;220:199–216.
3. Faiq MA, Dada T. Diabetes type 4: A paradigm shift in the understanding of glaucoma, the brain specific diabetes and the candidature of insulin as a therapeutic agent. Curr Mol Med. 2017;17:46–59.
4. Dada T. Is glaucoma a neurodegeneration caused by central insulin resistance: diabetes type 4? J Curr Glaucoma Pract. 2017;11:77–79.

Editors’ note: Dr. Di Polo has no financial interests related to her comments.

Contact information

Di Polo: diana@dsmmedia.com

Is vision restoration after glaucoma possible? Is vision restoration after glaucoma possible?
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