THERE’S A VIDEO on YouTube that shows a teenager stumbling through a dimly lit maze. He bumps into walls and makes achingly slow progress through to the other side. Then it shows the same man several months later, gliding through the setup with apparent ease.
The difference? The second run was after the young man had undergone gene therapy for a rare inherited form of degenerative blindness called Leber’s Congenital Amaurosis, (LCA) during which a virus carrier was injected into his eye to deliver copies of the correct version of his faulty gene.
These early trials, carried out in the UK and the US, the results of which were published in 2008, are considered landmark in scientific progress towards battling degenerative blindness such as LCA.
Continued research points the way to several potential and emerging treatments, which vary depending on the cause of the sight loss. They include ways to protect the light-sensitive cellular machinery at the back of the eye from dying away and even bionic devices that can replace the function of those cells after they are gone.
But first, the gene therapy. In many forms of inherited degenerative blindness, a clearer picture is emerging of the genetic changes that cause the problem, says Prof Jane Farrar from Trinity College Dublin. “When you get a mistake in a gene that is encoding a protein, the protein is wrongly shaped and cells can die prematurely,” she says.
If this happens to key cells at the back of the eye they are not replaced, and the result can be a progressive loss of vision.
Farrar and her Trinity colleagues, Prof Pete Humphries and Dr Paul Kenna, made an early breakthrough in understanding one form of inherited blindness, retinitis pigmentosa (RP). Around two decades ago they worked with large families where individuals had the condition. They uncovered changes, or mutations, in a key gene called rhodopsin, which encodes a pigment in the rod photoreceptor cells that help us see in dim light.
Since then, more than 150 disease-linked mutations have been characterised in RP, and the 2008 LCA trials have given the field of gene therapy a boost, says Farrar. “They demonstrated clearly that you can, within the context of the human eye, take a little virus that is not harmful to humans, engineer into it the correct gene and then use millions of years of viral evolution to be able to get into cell types in the human eye,” she says.
“You have a single sub-retinal injection of lots and lots of copies of the virus. The virus then infects the target cell types, and it starts expressing the gene that is missing.”
The trials demonstrated that the carrier virus they used was tolerated well in the human eye, she says. “The main problem with gene therapy has been that people have had an immune reaction to the virus and they haven’t tolerated it, whereas [this virus] was really well tolerated, and that has probably paved the way for lots of other studies.”
Farrar, Humphries and Kenna and a team of scientists Farrar describes as the “engine of this work” are now trying to develop a neat genetic therapy that can both suppress the troublesome mutated gene and also rescue the function of the eye cells in one fell swoop.
Farrar says the work, which is supported in part by Science Foundation Ireland and the charity Fighting Blindness Ireland and US, is moving forward in preclinical settings, and the company Genable Technologies has been set up to help bring the potential therapy closer to the market.
Other approaches are also emerging to stop eye cells dying away before their time. So-called “neuroprotection” aims to enhance remaining light-sensitive cells in the eye and prolong their function. And a team in Ireland recently discovered a potential source of neuroprotection from what seems an unusual source: Norgestrel, a component of the contraceptive mini-pill.
“Our work is looking to use standard pharmaceuticals to protect photoreceptors,” says Tom Cotter, professor of biochemistry at University College Cork. The college’s recent findings showed that the drug, which is taken by mouth, seemed to have a protective effect on these key cells in a preclinical model of retinal degeneration, and the researchers hope to look at the potential effects in humans.
Such approaches rely on cells being alive to start with, but what if the light-detecting machinery has already gone? Enter the bionic eye, which uses an electronic prosthetic device to replace the function of dead light-sensitive cells.
“The design is simple,” says Dr Gerald Chader from the Doheny Eye Institute in California, who was in Dublin last week to address the Fighting Blindness AGM.
“The patient wears an external camera, maybe perched on glasses, which captures light image and converts it to an electrical signal. That goes to a computer for processing, then the signal passes to an array of electrodes that are attached to the remaining cells in the eye and [the information is] passed down the optic nerve to the brain to produce a visual image.”
Chader works with Dr Mark Humayun, who developed one such prosthesis, the Argus, which was approved for sale in Europe earlier this year. “The current device, Argus II, affords previously blind retinal-degeneration patients some functional vision – letter and number reading and better mobility and orientation,” says Chader, who describes how people with RP have been able to scan everyday objects with the implant.
“Argus III is in prototype production. It has over 200 electrodes on the array implant, and Argus IV is on the drawing boards with over 1,000 electrodes. Theoretically, this should move the blind patient to face recognition and reading ability, two of the most important needs in independent living, working and a huge advance in quality of life.”
More generally, Chader describes as heartening the advances made over the last 20 years in research into potential therapies for blindness. “Good progress” has been made, he says. “But we are not finished by a long shot.”
Dietary supplements: Protection against degenerative blindness
Dr John Nolan of Waterford Institute of Technology is carrying out an international trial to examine the effects of specific dietary supplements to target age-related macular degeneration (AMD), where a pigment at the back of the eye breaks down.
“Age-related macular degeneration is the leading cause of age-related blindness in the developed world. People who develop this condition lose central vision, and so they lose the ability to perform normal activities such as reading, writing, driving a car and recognising their loved ones,” says Nolan, a principal investigator at the macular-pigment research group at WIT.
Macular pigment at the back of the eye is thought to have a protective effect by filtering blue light, says Nolan, who has been looking at how nutrition can affect levels of the pigment in the eye.
In particular, he is looking at the impact of taking dietary supplements of the pigment building blocks lutein, zeaxanthin and mesozeaxanthin; the latter, he says, could be a “silver bullet”.
“We get lutein from our diets but we get very little mesozeaxanthin: we are dependent on our body to generate it,” he says. “I have been able to show in pilot investigations that if you supply mesozeaxanthin in a supplement in people with deficient pigments, you can rebuild their pigments.”
Nolan has secured funding from the European Research Council to take that work further in a trial involving about 200 patients with AMD and more than 100 healthy young people.
“We have designed experiments that will measure visual contrast and will look at how they perform under the intensity of high-glare environments,” says Nolan.
“I believe if we can enrich and optimise this pigment in young, normal people, we can enhance visual experience and performance, so the hope for this project is that we can improve vision in the short-term in the young, normal population but also protect their vision into their later year
