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A treatment for blindness is edging closer, after a cutting-edge gene therapy has partially restored vision in six of ten patients.
The science behind “optogenetics”, which uses light to turn nerve cells on and off, won the Nobel Prize in Physiology or Medicine this week.
While a cure for blindness would certainly be impressive, optogenetics may also be used to treat deafness, pain and epilepsy.
The common factor behind all these different medical conditions is that they involve problems with the nervous system.
Nerve cells signal using pulses of electricity. There are already several useful medical devices that work by delivering electricity artificially, such as pacemakers to regulate the heart or brain implants to block tremor in Parkinson’s disease.
But this approach has limitations. The electric field from implanted electrodes leaks through the nerve cells surrounding the ones being targeted. That makes it hard to be precise and selectively activate only a few nerve cells.
That’s where optogenetics comes in. It was discovered in the 2000s that pond algae can swim towards the light because they have channels in their cell membrane that react to blue light by allowing entry of charged ions – the same mechanism behind electrical signals in animal nerve cells.
If the algal gene encoding that ion channel is inserted into rat nerve cells, then they also fire in response to light.
This gave scientists a new way to gain control over nerve cells in laboratory animals by implanting fibre-optic wires inside their heads. It gives more precision than using electrical wires, because light does not spread through biological tissue in the same way that an electric field does.
“Optogenetics provides opportunities for mapping the brain in a way that we could once only dream of,” said Professor Per Svenningsson, Chair of the Nobel Committee for Physiology or Medicine.
For a long time optogenetics was seen mainly as a research tool, but there has recently been progress with several medical applications too.
Reversing blindness
Treating blindness was the most obvious starting place, because the nerve cells at the back of the eye, within the retina, are naturally exposed to light, and so don’t require any fibre-optic implants.
The condition targeted, retinitis pigmentosa, is caused by progressive death of light-sensitive cells in the eye. The new approach involves recruiting different nerve cells within the retina to do the job of the ones that have died.
The treatment involves injecting the retina with a gene that makes them fire in response to amber light. Then, the patients wear special glasses that convert ordinary light into shades of amber.
It does not give normal vision: the recipients had to train with their glasses for several weeks to make sense of their strange new perceptions. “The initial response is that they see dots of light,” said Professor José-Alain Sahel, an ophthalmologist at the University of Pittsburgh, who led the research. “Then they try to make sense of the dots, what shapes they correspond to. It’s relearning vision.”
In the latest study, published in The New England Journal of Medicine, Sahel’s team reported that they had treated ten patients in one eye. Beforehand, they were either completely blind in that eye, or could, at best, detect if someone was waving a hand in front of their face.
After three months, six of the ten had meaningfully improved vision. That meant they could do tasks like picking up a cup from a table. They couldn’t, however, distinguish between different people’s faces.
But the next version of the technology may allow that, said Professor Sahel. His team are developing better versions by using several kinds of gene therapy that each target different cells in the retina, to give more visual discrimination.
Turning off pain or epilepsy with a switch
Chronic pain can be caused by misfiring of nerves, such as in trigeminal neuralgia, when there is overactivity of the large trigeminal nerve in the face. Those affected get shooting pains in their jaw and mouth, in short but agonising attacks.
Optogenetic therapy could help by making the nerve react to light. People could “turn off” the nerve pain either by holding a strong light source against their face – as some wavelengths of light can penetrate skin – or by activating an implanted light source with a wireless remote control.
US firm Modulight Biotherapeutics is due to start a clinical trial for trigeminal neuralgia within the next few years.
Modulight and other groups are also investigating epilepsy. Seizures are triggered by overactivity of brain cells, but people often detect warning signs beforehand. Optogenetic approaches would let people turn down their brain activity, like a dimmer switch.
Upgrade for cochlear implants
The next sense being targeted is hearing. We already have a good treatment for deafness called a cochlear implant. This is a tiny device surgically implanted inside the ear, which stimulates auditory nerves with electricity.
Cochlear implants are one of the most successful medical prosthetics ever developed, but they don’t provide normal hearing. Sounds are distorted and speech sounds almost robotic.
That is because a typical cochlear implant has about 12 electrodes registering sounds at different pitches. That compares with the 3,000 sound-sensitive cells in the human ear they are supposed to replace.
It is no use making implants with more electrodes because their electric field spreads out, each one stimulating more nerves than they are supposed to, blocking precise pitch discrimination.
But several groups are developing optogenetic cochlear implants that could have up to 100 electrode equivalents – which should give better pitch discrimination as each one can switch on a smaller number of cells.
The downside, though, is that this approach would require people to have a gene therapy applied to their ears before the cochlear implant is put in. At the moment, this is still at the stage of testing in animals; scientists are rightly cautious about gene therapies, as they may be irreversible.
The clinical applications of this approach are moving slowly: optogenetics was demonstrated on nerve cells in a dish in 2005 and the first person received the blindness treatment only in 2021.
But at a major meeting last year held by the Society for Neuroscience, researchers outlined a roadmap for translating optogenetics from a research technique to something that can help patients, as long as it can be proven safe.
“Vision is the golden example where we’re most advanced. But it’s not the only thing that’s going on,” said Professor Mark Hankins, a neuroscientist at the University of Oxford.
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