̽��ֱ�� of Cambridge - Cambridge Eye Trust

Gene therapy technique shows potential for repairing damage caused by glaucoma and dementia

cjb250 — Wed, 31 Mar 2021 18:00:54 +0000

Gene therapy – where a missing or defective gene is replaced by a healthy version – is becoming increasingly common for a number of neurological conditions including Leber’s Congenital Amaurosis, Spinal Muscular Atrophy and Leber’s Hereditary Optic Neuropathy. However, each of these conditions is rare, and monogenic – that is, caused by a single defective gene. ̽��ֱ��application of gene therapy to complex polygenic conditions, which make up the majority of neurodegenerative diseases, has been limited to date.

A common feature of neurodegenerative diseases is disruption of axonal transport, a cellular process responsible for movement of key molecules and cellular ‘building blocks’ including mitochondria, lipids and proteins to and from the body of a nerve cell. Axons are long fibres that transmit electrical signals, allowing nerve cells to communicate with other nerve cells and muscles. Scientists have suggested that stimulating axonal transport by enhancing intrinsic neuronal processes in the diseased central nervous system might be a way to repair damaged nerve cells.

Two candidate molecules for improving axonal function in injured nerve cells are brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB).

In research published today in Science Advances, scientists at the ̽��ֱ�� of Cambridge show that delivering both of these molecules simultaneously to nerve cells using a single virus has a strong effect in stimulating axonal growth compared to delivering either molecule on its own. They tested their idea in two models of neurodegenerative disease known to be associated with reduced axonal transport, namely glaucoma and tauopathy (a degenerative disease associated with dementia).

Dr Tasneem Khatib from the John van Geest Centre for Brain Repair at the ̽��ֱ�� of Cambridge, the study’s first author, said: “ ̽��ֱ��axons of nerve cells function a bit like a railway system, where the cargo is essential components required for the cells to survive and function. In neurodegenerative diseases, this railway system can get damaged or blocked. We reckoned that replacing two molecules that we know work effectively together would help to repair this transport network more effectively than delivering either one alone, and that is exactly what we found.

“This combined approach also leads to a much more sustained therapeutic effect, which is very important for a treatment aimed at a chronic degenerative disease.

“Rather than using the standard gene therapy approach of replacing or repairing damaged genes, we used the technique to supplement these molecules in the brain.”

Glaucoma is damage to the optic nerve often, but not always, associated with abnormally high pressure in the eye. In an experimental glaucoma model, the researchers used a tracer dye to show that axonal transport between the eye and brain was impaired in glaucoma. Similarly, a reduction in electrical activity in the retina in response to light suggested that vision was also impaired.

Dr Khatib and colleagues used ‘viral vectors’ – gene therapy delivery systems – to deliver TrkB and BDNF to the retina of rats. They found that this restored axonal transport between the retina and the brain, as observed by movement of the dye. ̽��ֱ��retinas also showed an improved electrical response to light, a key prerequisite for visual restoration.

Next, the team used transgenic mice bred to model tauopathy, the build-up of ‘tangles’ of tau protein in the brain. Tauopathy is seen in a number of neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia. Once again, injection of the dye showed that axonal transport was impaired between the eye and the brain – and that this was restored using the viral vectors.

Intriguingly, the team also found preliminary evidence of possible improvement in the mice’s short-term memory. Prior to treatment, the researchers tested the mice on an object recognition task. ̽��ֱ��mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object. ̽��ֱ��researchers measured the amount of the time the mouse spent exploring each object to see whether it had remembered the object from the previous task.

This task was repeated after the viral vector had been injected into the mouse’s brain and the results were suggestive of a small improvement in short-term memory. While the results of this particular study did not quite achieve statistical significance – a measure of how robust the findings are – the researchers say they are promising and a larger study is now planned to confirm the effect.

Professor Keith Martin from the Centre for Eye Research Australia and the ̽��ֱ�� of Melbourne, who led the study while at Cambridge, added: “While this is currently early stage research, we believe it shows promise for helping to treat neurodegenerative diseases that have so far proved intractable. Gene therapy has already proved effective for some rare monogenic conditions, and we hope it will be similarly useful for these more complex diseases which are much more common.”

̽��ֱ��research was supported by Fight for Sight, Addenbrooke’s Charitable Trust, the Cambridge Eye Trust, the Jukes Glaucoma Research Fund, Quethera Ltd, Alzheimer's Research UK, Gates Cambridge Trust, Wellcome and the Medical Research Council.

Reference
Khatib, TZ et al. Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axon transport with functional recovery. Science Advances; 31 Mar 2021; DOI: 10.1126/sciadv.abd2590

Scientists at the ̽��ֱ�� of Cambridge have shown in animal studies that gene therapy may help repair some of the damage caused in chronic neurodegenerative conditions such as glaucoma and dementia. Their approach demonstrates the potential effectiveness of gene therapy in polygenic conditions – that is, complex conditions with no single genetic cause.

[Our] approach also leads to a much more sustained therapeutic effect, which is very important for a treatment aimed at a chronic degenerative disease

Tasneem Khatib

IAPB/VISION 2020

Screening for glaucoma

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Technique to regenerate the optic nerve offers hope for future glaucoma treatment

cjb250 — Thu, 05 Nov 2020 10:00:30 +0000

Axons – nerve fibres – in the adult central nervous system (CNS) do not normally regenerate after injury and disease, meaning that 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, scientists tested whether the gene responsible for the production of a protein known as Protrudin could stimulate the regeneration of nerve cells and protect them from cell death after an injury.

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

Nerve cells in the retina, known as retinal ganglion cells, extend their axons from the eye to the brain through the optic nerve in order to relay and process visual information. To investigate whether Protrudin might stimulate repair in the injured CNS 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 enabled the axons to regenerate over large distances. They also found that the retinal ganglion cells were protected from cell death.

̽��ֱ��researchers showed that this technique may 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 elevated pressure inside the eye. If not diagnosed early enough, glaucoma can lead to loss of vision. In the UK, round one in 50 people over the age of 40, and one in ten people over the age of 75 is affected by glaucoma.

To demonstrate this protective effect of Protrudin against glaucoma, the researchers used a whole retina from a mouse eye and grew it in a cell-culture dish. Usually around a half of retinal neurons die within three days of retinal removal, but the researchers found that increasing or activating Protrudin led to almost complete protection of retinal neurons.

Dr Veselina Petrova from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author, said: “Glaucoma is one of leading causes of blindness worldwide. ̽��ֱ��causes of glaucoma are not completely understood, but there is currently a large focus on identifying new treatments by preventing nerve cells in the retina from dying, as well as trying to repair vision loss through the regeneration of diseased axons through the optic nerve.

“Our strategy relies on using gene therapy – an approach already in clinical use – to deliver Protrudin into the eye. It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow. It’s important to point out that these findings would need further research to see if they could be developed into effective treatments for humans.”

Protrudin normally resides within the endoplasmic reticulum, tiny structures within our cells. In this study, the team showed 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 process of regeneration after injury. Protrudin stimulates transport of these materials to the site of injury.

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

“ ̽��ֱ��optic nerve injury model is often used to investigate new treatments for stimulating CNS axon regeneration, and treatments identified this way often show promise in the injured spinal cord. It’s possible that increased or activated Protrudin might be used to boost regeneration in the injured spinal cord.”

̽��ֱ��research was supported by the Medical Research Council, Fight for Sight, the Bill and Melinda Gates Foundation, Cambridge Eye Trust and the National Eye Research Council.

Reference
Petrova, V et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Comms; 5 Nov 2020; DOI: 10.1038/s41467-020-19436-y

Scientists have used gene therapy to regenerate damaged nerve fibres in the eye, in a discovery that could aid the development of new treatments for glaucoma, one of the leading causes of blindness worldwide.

It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow

Veselina Petrova

TobiasD

Eye

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