University of Cambridge research suggests gene therapies offer promise in glaucoma and dementia
Promising research at the University of Cambridge suggests gene therapies could help repair some of the damage caused in chronic neurodegenerative conditions such as glaucoma and dementia.
Their studies in animals offer hope that such therapies could be effective in ‘polygenic’ conditions, which are complex and do not have a single genetic cause.
Gene therapies involve replacing a missing or defective gene with a healthy version.
They have become increasingly common, but typically for rare and ‘monogenic’ conditions – those caused by a single defective gene, such as Leber’s congenital amaurosis, spinal muscular atrophy and Leber’s hereditary optic neuropathy.
There have been limited applications of such therapies to polygenic conditions, which include the majority of neurodegenerative conditions.
In their new research, Cambridge scientists delivered two candidate molecules simultaneously to nerve cells using a single virus to achieve a strong effect on axonal growth.
Dr Tasneem Khatib, from the John van Geest Centre for Brain Repair at the University of Cambridge, the study’s first author, explained: “The 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.”
Axons are long fibres that transmit electrical signals, allowing nerve cells to communicate with one another and with muscles.
Axonal transport is a cellular process that moves key molecules and cellular building blocks such as mitochondria, lipids and proteins to and from the body of a nerve cell.
It has been suggested that stimulating this process by enhancing intrinsic neuronal processes in the diseased central nervous system could be a way of repairing damaged nerve cells.
The Cambridge team explored this idea using two candidate molecules for improving axonal function – brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB).
They tested the idea in two models of neurodegenerative disease known to be associated with reduced axonal transport – glaucoma and tauopathy, a degenerative disease associated with dementia.
Glaucoma involves damage to the optic nerve and is typically associated with abnormally high pressure in the eye.
Using rats, researchers deployed a tracer dye to show axonal transport between the eye and brain was impaired in glaucoma, while a reduction in electrical activity in the retina in response to light suggested vision was also impaired.
Dr Khatib and colleagues then used ‘viral vectors’ – which are gene therapy delivery systems – to deliver the two molecules to the retina of rats. The movement of the dye showed this restored axonal transport between the retina and the brain and the retinas also showed an improved electrical response to light, which is a prerequisite for visual restoration.
Next they used transgenic mice bred to model tauopathy, which is the build-up of ‘tangles’ of tau protein in the brain.
Tauopathy is seen in neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia.
Injecting the dye again enabled the team to show that axonal transport was impaired between the eye and the brain and that it was restored using the viral vectors.
They even found preliminary evidence of possible improvement in the mice’s short-term memory using an object recognition task.
Before the treatment, a 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.
Shortly after, 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.
The 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.
After the viral vector had been injected into the mouse’s brain, the test was repeated and suggested a small improvement in short-term memory. The result here was not deemed statistically significant, but the researchers were encouraged and plan a larger study to confirm it.
Professor Keith Martin, from the Centre for Eye Research Australia and the University of Melbourne, who led the study while at Cambridge, said: “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.”
In the study, published in Science Advances, the researchers write: “We feel that these findings do have implication for clinical practice.”
The 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.