Gene therapy: glaucoma and dementia

Gene therapy research repairs nerve transport systems damaged by glaucoma and dementia: Results of the pre-clinical study, led by Professor Keith Martin from the Centre for Eye Research Australia and University of Melbourne and Dr Tasneem Khatib from the University of Cambridge, are published today in Science Advances.

Researchers say the findings in experiments on mice show promise for developing new gene therapies to treat both glaucoma and dementia.

But critically, the findings also demonstrate how gene therapies could treat complex neurodegenerative diseases that are caused multiple factors rather than a single genetic fault.

“Currently many gene therapies are targeted at rare diseases caused by a single genetic fault, where a missing or damage gene can be replaced to treat the condition,’’ says Professor Martin.

“More common neurodegenerative diseases like glaucoma or dementia are much more complex and caused by a range of genetic and other contributing factors.

“Although the research is in early stages, it shows promise for developing gene therapies for many of these common diseases to complement existing therapies.’’

Axons and the optic nerve

Professor Martin says the research also demonstrates gene therapy’s potential to support optic nerve function by improving its ability to transport vital materials and information between the eye and brain.

Axons are long nerve fibres which transport electrical signals that allow nerve cells to communicate with other nerve cells and muscles.

In many neurodegenerative diseases this transport system is disrupted, leading to chronic, progressive disease.

In glaucoma, the breakdown of signal transmission along the optic nerve leads to vision loss and blindness. In dementia, the build-up of tau proteins ‘tangles’ in the brain disrupts vital communication between brain cells, causing memory loss and cognitive decline.

About the research

In pre-clinical experiments, the researchers tested a new gene therapy to determine if it could stimulate axon growth and improve optic nerve function.

They combined two key molecules into a single viral vector and delivered it to mice affected by glaucoma and dementia.

Before the therapy, both groups had impaired optic nerve function with reduced transmission of electrical signals between the eye and brain. Those with glaucoma also showed signs of reduced vision.

However, after the therapy was delivered, optic nerve activity improved in both groups and the mice with glaucoma showed signs of improved vision.

There was also a possible small improvement in the mice’s short-term memory, which researchers now plan to test in a larger study to confirm the effect.

Combined gene therapy technique

The study also took a new approach to delivering gene therapy by combining two molecules thought to improve axon function – brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) – in one treatment.

Typically, most gene therapies deliver only one molecule or gene in a treatment.

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

“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. “

Dr Khatib noted that the combined approach led to a more sustained therapeutic effect, which is very important for the treatment of chronic degenerative diseases.

More information

The research was funded in the UK 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 (UK).

Read the full study

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 March 2021.