Scientists use gene therapy to regenerate damaged optic nerve fibers

Reviewed by Emily Henderson, B.Sc.November 5, 2020

Scientists have used gene therapy to regenerate damaged nerve fibers in the eye, in a discovery that could help develop new treatments for glaucoma, a leading cause of blindness worldwide.

Axons – nerve fibers – in the adult central nervous system (CNS) do not normally regenerate after injury and disease, which means the damage is often irreversible. However, over the past decade there have been a number of discoveries that suggest it may be possible to stimulate regeneration.

In a study published today in Nature Communications, the scientists tested whether the gene responsible for producing a protein known as Protrudin could stimulate nerve cell regeneration and protect them from cell death after injury.

The team, led by Dr Richard Eva, Professor Keith Martin and Professor James Fawcett of the John van Geest Center for Brain Repair at the University of Cambridge, used a cell culture system to grow brain cells in a dish. They then injured their axons using a laser and analyzed the response to this injury using live cell microscopy. The researchers found that increasing the amount or activity of Protrudin in these nerve cells greatly increases their ability to regenerate.

Nerve cells in the retina, known as retinal ganglion cells, extend their axons from the eye to the brain via the optic nerve to transmit and process visual information. To investigate whether protrudin could stimulate repair in the damaged central nervous system in an intact organism, the researchers used a gene therapy technique to increase the amount and activity of protrudin in the eye and optic nerve. When they measured the amount of regeneration a few weeks after a crush injury to the optic nerve, the team found that Protrudin had allowed the axons to regenerate over large distances. They also found that the retinal ganglion cells were protected from cell death.

Researchers have shown that this technique can help protect against glaucoma, a common eye condition. In glaucoma, the optic nerve that connects the eye to the brain is progressively damaged, often in association with high pressure within the eye. If not diagnosed early enough, glaucoma can lead to vision loss. In the UK, around one in 50 people over the age of 40 and one in ten people over the age of 75 have glaucoma.

To demonstrate this protective effect of Protrudin against glaucoma, the researchers used an entire retina from a mouse eye and cultured it in a cell culture dish. Usually about half of the retinal neurons die within three days of retinal removal, but the researchers found that the increase or activation of Protrudin led to almost complete protection of the retinal neurons.

Glaucoma is a leading cause of blindness around the world. The causes of glaucoma are not fully understood, but there is currently a great deal of attention in identifying new treatments by preventing the death of nerve cells in the retina, as well as trying to repair vision loss through the regeneration of diseased axons through the optic nerve. .

Our strategy is based on using gene therapy – an approach already in clinical use – to deliver Protrudin into the eye. It is possible that our treatment could be further developed as a way to protect retinal neurons from death, as well as stimulate their axons to grow back. Importantly, these findings would need more research to see if they could be developed into effective treatments for humans. “

Dr. Veselina Petrova, Department of Clinical Neuroscience, University of Cambridge, the first author of the study

Protrudin normally resides in the endoplasmic reticulum, small structures within our cells. In this study, the team demonstrated that the endoplasmic reticulum found in axons appears to provide materials and other cellular structures important for growth and survival in order to support the regeneration process after injury. Protrudin stimulates the transport of these materials to the injury site.

Dr Petrova added: “Nerve cells in the central nervous system lose the ability to regenerate their axons as they mature, so they have very limited ability to regrow. This means that the injuries to the brain, spinal cord and nerve opticians have life-altering consequences.

“The optic nerve injury model is often used to study new treatments to stimulate CNS axon regeneration, and treatments identified in this way often show promise in the damaged spinal cord. It is possible that increased or activated protrudin could be used to stimulate regeneration in the damaged spine. cord. “