Glaucoma is the leading cause of irreversible blindness around the globe. With population growth, aging demographics, and urbanisation, roughly 110 million people worldwide are expected to have glaucoma by 2040. This stark projection highlights the need for effective glaucoma treatment, not always provided by traditional medical techniques. Where conventional medicine fails, gene therapies — drugs with therapeutic genetic material (RNA or DNA) — could constitute an exciting alternative.
Trinity researchers, led by Prof. Jane Farrar, Dr. Sophia Millington-Ward, Dr. Arpad Palfi, and Dr. Naomi Chadderton have designed a glaucoma gene therapy, AAV-NDI1, that has yielded promising results on disease models. This exciting development earned their paper a place in the International Journal of Molecular Sciences last August.
Trinity News spoke to the geneticists involved to understand why the AAV-NDI1 gene therapy is needed and how it works. Here is the story of AAV-NDI1 so far.
A gap in conventional medicine
“Lacking obvious initial symptoms, this “silent blinder” can cause early irreversible damage, unbeknownst to affected individuals”
Glaucoma is an eye condition typically caused by damage to the optic nerve and loss of retinal ganglion cells (RGCs). These cells are critical to communicate visual information to the brain. Hence, glaucoma patients progressively lose their field of vision as RGCs undergo cell death. Lacking obvious initial symptoms, this “silent blinder” can cause early irreversible damage, unbeknownst to affected individuals. Unfortunately, the disease is not yet fully understood, caused by a combination of environmental and genetic factors.
Risk factors known to contribute to RGC loss include age, family history, lifestyle and increased intraocular (eye) pressure or IOP. Current glaucoma treatments focus on reducing IOP via surgery or laser treatment. The outcomes of these treatments vary, with vision loss often continuing afterward., Phenotypes (symptoms) also vary; not all glaucoma patients have high IOP that needs to be reduced in the first place.
Overall, current glaucoma treatments, while benefiting some patients, do not consistently control disease progression.
However, as our ability to sequence or “read” the 3 billion letters of human genetic code has improved over recent decades, so too has our understanding of human disease. This is the basis for research by the human genetics team at Trinity, who are harnessing the power of our genetic code in order to understand and treat inherited retinal diseases like glaucoma.
Design strategy: An energy boost
The recently published glaucoma gene therapy design (AAV-NDI1) is based on treating mitochondrial dysfunction, a defect commonly seen in neurodegenerative disorders.
Often described as the “powerhouse of the cell”, mitochondria produce ATP, the ‘currency’ of cellular energy. Damaged mitochondria produce less ATP and thus have decreased ability to generate cellular energy and put the cell under oxidative stress.
“As you can imagine, mitochondria feeling ‘under the weather’ has catastrophic consequences for the eye”
The retina has one of the highest energy demands of all bodily tissues. As you can imagine, mitochondria feeling ‘under the weather’ has catastrophic consequences for the eye. Mitochondrial damage is evident in the RGCs of glaucoma patients, likely contributing to cell loss.
What causes mitochondrial damage is not clear, however. Unlike single gene “Mendelian” eye conditions also involving RGCs and the optic nerve, like leber Hereditary Optic Neuropathy (LHON), there isn’t a singular genetic mutation or “typo” causing mitochondrial problems in glaucoma patients.
AAV-NDI1 thus works “gene-independently”. It does not target a gene that has gone wrong, but instead adds a gene that will help cellular function. As Dr Sophia Millington-Ward, co-author of the paper, explains, the gene added gives mitochondria an “energy boost”. If RGCs are “sick but not dead”, this energy boost could prevent further cell death.
How does AAV-NDI1 work?
AAV-NDI1 therapy targets an important pathway of energy generation: the electron transport chain (ETC). In this chain, electrons are passed from one protein complex to another, gathering energy until ATP can be produced.
Using modified viruses as delivery vessels (vectors), the Trinity team wanted to supply mitochondria with extra copies of a gene coding for a protein that has a similar role to the first protein conglomerate in the ETC, called Complex I. But multiple genes are needed to make Complex I, each separately encoding a subunit (part) of Complex I, so to avoid interfering with the ETC in already weakened RGCs the Trinity team needed to supply mitochondria with a simpler version of Complex I.
As the ETC is such a vital pathway for energy production, it is conserved across evolution. This means that different versions of the same protein are found across the Tree of Life.
The team used the yeast equivalent of Complex I, called “NDI1”. Having only one protein part, NDI1 doesn’t interfere with native human proteins but can still contribute to ETC activity. Therefore, the yeast gene encoding NDI1 can be administered to humans to increase their mitochondrial activity. The team at Trinity created an enhanced version of NDI1, optimised for treatment of optic neuropathies.
The idea of using NDI1 to treat damaged human mitochondria was first suggested in the early 2000s. Since then, NDI1 has been investigated as a treatment for a variety of neurodegenerative diseases, including Parkinson’s.
Promising results
When tested on glaucoma models, NDI1 improved mitochondrial function. Human retinal cells displayed increased oxygen consumption and ATP production, as well as decreased oxidative stress. Even low doses provided benefits.
These results are exciting not only for the future of glaucoma therapy, but mitochondrial diseases in general. Dr. Millington-Ward says: “potentially the approach may be valuable for multiple ocular conditions where the mitochondria aren’t working as well as they should”.The lab previously showed the same therapy benefitted models of Age-related Macular Degeneration (AMD), for example.
Future perspectives
“Getting a gene therapy from the lab to the clinic is a long and challenging process”
Getting a gene therapy from the lab to the clinic is a long and challenging process. Firstly, improved mitochondrial function is an encouraging indicator of better RCG health but does not necessarily mean prolonged cell survival in glaucoma patients. This can only be confirmed with further research.The therapy must also undergo several safety tests, including toxicology and biodistribution trials.
The competitive drug discovery funnel is difficult, and given the cost of human clinical trials the money needed is in the millions.“What we would love to do is obviously bring it to patients eventually however that requires significant funding,” remarks Dr. Millington-Ward. The lab is up for the challenge, however, as evidenced by the establishment of their spinoff business, Vzarii Therapeutics.
AAV-NDI1 represents a clever gene therapy design which improves the mitochondrial function of RGCs by providing an“energy boost” to degenerating cells in glaucoma patients, preventing further vision loss. Although more research needs to be done, AAV-NDI1’s gene-independent design implies potential therapeutic value for multiple ocular conditions such as glaucoma and AMD.
Though the researchers have challenges ahead in getting this gene therapy further developed and into the clinic, they remain determined to fight for a future with effective and safe glaucoma treatment.
The research was funded by Science Foundation Ireland, Enterprise Ireland, Health Research Board Ireland, EU Marie Curie Innovative Training Network, and Fighting Blindness Ireland—Health Research Charities Ireland.
