Stem-cell models reveal glaucoma secrets  

Garvan Institute of Medical Research, Media releases

Australian researchers uncover hidden genetic markers of glaucoma.

Stem cell models of the retina and optical nerve have been used to identify previously unknown genetic markers of glaucoma, in research jointly led by scientists from the Garvan Institute of Medical Research, the University of Melbourne, and the Centre for Eye Research Australia. The findings open the door to new treatment for glaucoma, which is the world’s leading cause of permanent blindness.

“We saw how the genetic causes of glaucoma act in single cells, and how they vary in different people. Current treatments can only slow the loss of vision, but this understanding is the first step towards drugs that target individual cell types,” says Professor Joseph Powell, joint lead author at the Garvan Institute of Medical Research.

The research, published today in the journal Cell Genomics, comes out of a long-running collaboration between Australian medical research centres to use stem-cell models to uncover the underlying genetic causes of complicated diseases.

Glaucoma damages cells in the optic nerve, the part of the eye that receives light and sends it to the brain. It is impossible to take samples from this part of the eye in a non-invasive way, which limits research.

Instead, to create samples for the study, researchers took skin biopsies from participants with and without glaucoma. The skin cells were reprogrammed to revert to stem cells, and then guided into becoming retinal cells.

With 110 successfully converted samples, researchers sequenced more than 200,000 individual cells to generate ‘molecular signatures’. Comparing signatures with and without glaucoma revealed key genetic components that control how the disease attacks the retina.

Studying glaucoma inside retinal cells created a ‘context-specific profile’ of the extremely complicated disease, says co-lead author Professor Pébay.

“We wanted to see how glaucoma acts in retinal cells specifically—rather than in a blood sample, for instance—so we can identify the key genetic mechanisms to target. Equally, we need to know which genetic variations are healthy and normal, so we can exclude them from a treatment,” she says.

Across both healthy and diseased samples, researchers identified 312 genetic variants associated with the target retinal cells. Further analysis found 97 genetic clusters linked to the damage caused by glaucoma.

The study’s third lead author, Professor Alex Hewitt, says the findings lay the foundation for research into new glaucoma treatments:

“Not only can scientists develop more tailored drugs, but we could potentially use the stem-cell models to test hundreds of drugs in pre-clinical assays. This method could also be used to assess drug efficacy in a personalised manner to assess whether a glaucoma treatment would be effective for a specific patient.”

Media contact:

Maddy De Gabriele, Science in Public,

Co-Lead authors of the study are:

  • Professor Jospeh Powell, Pillar Director Cellular Science, Garvan Institute of Medical Research
  • Professor Alice Pébay, Department of Anatomy and Physiology, Department of Surgery, The University of Melbourne
  • Professor Alex Hewitt, the Centre for Eye Research Australia and the Menzies Institute for Medical Research at the University of Tasmania


Professor Joseph Powell, Pillar Director Cellular Science, Garvan Institute of Medical Research. Credit: Garvan Institute

The study used skin samples to generate stem cell models, and then carried out detailed single-sell genetic sequencing. Credit: Garvan Institute

A simulation of eyesight loss from glaucoma, which is currently irreversible. Glaucoma is the worldwide leading cause of permanent blindness. Credit: National Institutes of Health

Supporting information:

About Glaucoma

Glaucoma is the leading cause of blindness worldwide and is predicted to affect about 80 million people by 2040. Treatments options are currently extremely limited.

The most common form of glaucoma (primary open-angle glaucoma, or POAG) causes the degeneration of retinal ganglion cells, which are neurons near the inner eye. This leads to a gradual and irreversible loss of vision.

POAG is likely to be inherited from a parent and is a very genetically complex disease. The only available treatment is to release pressure in an affected eye, which slows the loss of sight but can’t stop or reverse the process.

About Gene Profiling

The researchers used single-cell RNA genetic sequencing to examine individual cells, which creates a very detailed genetic ‘map’.

This research is possible due to advances in three key areas: the development of single-cell sequencing technology that shows relationships between individual cells; the ability to produce, reprogram and differentiate stem cells at scale; and advances in machine learning to analyse the incredible data sets.

Profiling complicated genetic diseases such as glaucoma improves our understanding of its underlying mechanisms, possible causes and risk factors.

The researchers used a kind of genetic mapping which looks for genetic variations that affect the expression of one or more genes. Identifying these key genes can be used to further deduce how common genetic variations influence glaucoma.

Genetic investigations help build complete human models of disease, which are crucial for drug development and pre-clinical trials. The success of this research highlights the power of large-scale studies using stem-cell models to uncover new genetic indicators of specific diseases.


To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.


Maciej Daniszewski1,2,3,13, Anne Senabouth4,13, Helena H. Liang2,3, Xikun Han5, Grace E. Lidgerwood1,2,3, Damián Hernández1,2,3, Priyadharshini Sivakumaran3, Jordan E. Clarke3, Shiang Y. Lim2,6, Jarmon G. Lees6,7, Louise Rooney1,2,3, Lerna Gulluyan1,2,3, Emmanuelle Souzeau8, Stuart L. Graham9, Chia-Ling Chan4, Uyen Nguyen4, Nona Farbehi4, Vikkitharan Gnanasambandapillai4, Rachael A. McCloy4, Linda Clarke3, Lisa Kearns3, David A. Mackey10,11, Jamie E. Craig8, Stuart MacGregor5, Joseph E. Powell4,12,13, Alice Pébay1,2,3,13, and Alex W. Hewitt2,3,11,13,14


  1. Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
  2. Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia
  3. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
  4. Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW2010, Australia
  5. QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
  6. O’Brien Institute Department of St Vincent’s Institute of Medical Research, Melbourne, Fitzroy, VIC 3065, Australia
  7. Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Parkville, VIC 3010, Australia
  8. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia
  9. Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia
  10. Lions Eye Institute, Centre for Vision Sciences, University of Western Australia, Crawley, WA 6009, Australia
  11. School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, Australia
  12. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW 2052, Australia