Eyes forward

Macular degeneration is a leading cause of blindness – and emerging techniques to treat it could see the end of painful eye injections. Lou Reade reports

Of all places to have an injection, the eyeball is probably near the bottom of anybody’s list. Yet this is how macular degeneration – the leading cause of sight loss in the developed world – is commonly treated.

In the UK, nearly 1.5m people are affected by macular disease, according to the Macular Society. In its commonest ‘wet’ form, macular degeneration is caused by the growth of rogue blood vessels at the back of the eye, due to over-production of a protein called vascular endothelial growth factor (VEGF). The blood vessels leak, causing damage to the central part of the retina – the macula – and a loss of central vision. Regular injections of so-called anti-VEGF drugs help to alleviate the problem.

As well as being time-consuming, these injections can be stressful and upsetting for sufferers, many of whom are elderly. Because the condition is prevalent among older people, it is usually referred to as age-related macular degeneration, or AMD. However, a number of emerging treatments – including eye drops, inserts and a modified ‘contact lens’ – could spell the end of regular injections, and treat the condition less invasively.

At the same time, emerging stem cell therapy, which has reversed sight loss for two patients with the ‘dry’ form of macular degeneration, could find wider use within a few years.

Drop goal
UK researchers have developed what sounds the most obvious alternative to injections – delivering the medication in the form of eye drops.

There are many advantages to applying anti-VEGF drugs in this way: it is less invasive; it is more controllable – as a higher dose simply requires another eye drop rather than a ‘second injection’, which could increase pressure in the eye; and it is more convenient, because the medication can be applied at home rather than requiring a hospital visit. This, in turn, reduces the clinical burden and helps to save costs.

However, developing a formulation that can penetrate the eye is no easy task.

‘The eye is designed to be as closed as possible,’ says Felicity de Cogan, research fellow in the school of clinical and experimental medicine at Birmingham University, who led the effort to develop the eye drops.

Eye drops are already used to treat conditions such as glaucoma. But in this case, the medication used – a steroid – is a very small molecule that can easily penetrate into the eye.

‘An anti-VEGF drug like Lucentis is a huge molecule,’ she says. ‘Also, it needs to reach the back of the eye.’

The researchers have designed a series of cell penetrating peptides (CPPs) that are mixed with a drug like Lucentis to ‘drag it to the back of the eye’. The CPPs are small proteins that act as ‘penetration enhancers’ – opening up pores in cells for long enough to allow medication to pass through.

Although the drug needs to get to the back of the eye, it is enough for it to reach the jelly-like vitreous humour into which these drugs are normally injected. ‘In this way, we are mimicking what happens with an injection,’ says de Cogan.v The earliest formulations simply tested whether it was possible to penetrate the eye; later tests, on mice, proved that the formulation was effective in treating symptoms. The latest trials repeated this in pigs and rabbits, whose eyes are similar in size to a human’s. ‘These tests proved that the drug could diffuse right to the back of the eye,’ she says.

At the same time, further tests showed that the CPPs, which have a poly-arginine structure, were non-toxic, and formed complexes with the anti-VEGF drug. The complexes were cleared from the back of the eye within 24 hours, suggesting that a daily dose of drops would be needed. The researchers say that this method of treatment ‘was as efficacious as a single [intravitreal] injection’ (Investigative Ophthalmology & Visual Science, doi:10.1167/iovs.16-20072).

While a typical injection contains around 300 micrograms of anti-VEGF drug, which is slowly consumed over the course of a month, the eye drops might deliver a daily dose of 3-4 micrograms, says de Cogan. The patent on the technique has now been transferred to US pharmaceuticals company Macregen, which is looking to organise a clinical trial of the drug as early as this year.

Making contact
At the same time, scientists at Nanyang Technological University (NTU) in Singapore have recently developed a modified ‘contact lens’ patch that could provide a painless alternative to eye injections (Nature Commun., doi: 10.1038/s41467-018-06981-w).

Its surface is covered with biodegradable microneedles that deliver drugs into the eye in a controlled way. After briefly – and gently – pressing the patch onto the surface of the eye akin to applying a contact lens, the drug-filled microneedles remain embedded in the cornea – releasing the drug over time as they dissolve.

Research leader Professor Chen Peng, from the School of Chemical and Biomedical Engineering, says: ‘The microneedles are made of a substance found naturally in the body, and tests on mice have shown they are painless and minimally invasive. If we successfully replicate the same results in human trials, the patch could become a good option for eye diseases that require long-term management at home.’

The 2mm square patch has nine microneedles – each thinner than a strand of hair and made from hyaluronic acid, a substance found in the eye and often used in eye drops.

Chen’s team has filed a patent for the device and is looking into the feasibility of conducting clinical trials.

Eye implant
Genentech, which developed Lucentis, has completed a Phase 2 clinical trial for a refillable implant that could deliver medicine continuously rather than via repeated injections.

The company says that its Port Delivery System (PDS) – which is about the size of a grain of rice – can be implanted into the eye and refilled when required. The device is not visible on the outside of the eye, as it is implanted under the eyelid. After implantation, it can be refilled during a visit to the surgery.

The trial, which involved 220 patients, found that the device needed refilling around every six months – and as long as 15 months for some patients.

‘If the PDS is successful, it could have a major impact on the way we treat people with wet macular degeneration,’ says Carl Regillo, chief of retina service at Wills Eye Hospital in Philadelphia, US, and an investigator for the study.

Recruitment has begun for Phase 3 trials, which are expected to involve around 360 patients. Regillo estimates that the PDS could be available within three years.

Soft artificial retinas
Looking further ahead, scientists at the University of Texas at Austin, US, have developed ‘soft’ 2D materials to make artificial retinas designed to conform to the natural shape of the eyeball.

The materials combine molybdenum disulfide, which acts as a photosensitive semiconductor, with graphene interconnectors to form a very thin 2D layer. This converts light into an electronic signal that stimulates the optic nerve to give light perception.

‘Existing retinal implants are made of silicon, which is very rigid and puts a strain on the eye,’ says Nanshu Lu, talking at the American Chemical Society (ACS) meeting in Boston in August 2018. ‘It also leads to a ‘flat’ image on the retina.’

The team has formed the new materials into a ‘truncated icosahedron’ – a flat shape that folds up into a near-hemisphere – just 1cm in diameter and 1 micron thick that holds an array of 1,935 phototransistors.

‘It imposes no mechanical burden on the retina,’ she says. So far, the team has only worked with rats, but hopes to move to larger animal models in future. For now, the materials are also much more expensive than silicon, she adds – and have some way to go to match actual vision.

‘We are still quite far away from ‘real’ human vision in terms of things like pixels and colour-matching, but we see this as a first step towards ultimate super-high density and all-colour range vision in the future,’ she says.

Dry treatment
While there are many treatments for ‘wet’ macular degeneration, the same is not true of the ‘dry’ form – but this may be changing. In February 2019, for instance, researchers at Oxford University announced a world-first gene therapy treatment – injecting a synthetic gene into the eye of an 80-year-old woman to treat her dry macular degeneration.

A more established UK project – called the London Project to Cure Blindness – has also developed a successful treatment for ‘dry’ macular degeneration. This has been achieved by growing new stem cells and implanting them at the correct place in the macula.

Lyndon da Cruz, a leading macular degeneration researcher based at Moorfields Eye Hospital in London, and one of the driving forces behind the London Project, says: ‘The eyeball is about the size of a table tennis ball, and the macula is about the same thickness. It has three separate layers – and these are critical in understanding what we’ve achieved.’

The first layer is the nerve layer, and includes the rods and cones that are critical to sight; the middle ‘retinal pigment epithelium’ (RPE) layer has two jobs – it nourishes the nerve layer, and acts as a physical barrier to separate it from the third layer, which contains blood vessels.

Macular degeneration occurs when one of the two functions of the RPE layer – physical separation or nerve nourishment – are lost.

In ‘wet’ macular degeneration, blood vessels grow through to the nerve layer; in the ‘dry’ form, nerve cells die because they are no longer being nourished.

‘Medicine is very good at ‘destroying’ things – such as extra blood vessels: we can laser them, cut them out, or remove them using drugs,’ he says.

Nevertheless, loss of cells is far harder to solve. ‘The hardest thing to replace in medicine is nerve cells,’ he says. ‘This is why there are so many treatments for wet macular degeneration, but not for dry.’

However, the London Project has successfully reversed the sight loss of two patients. The patients were at a specific point in the disease – in that the RPE layer had ‘failed’, but the effect had not yet spread to the other layers.

The researchers were able to grow critical cells for the RPE layer, ‘consistently and safely’, says da Cruz, and implant them into the eye. This could offer a treatment for both wet or dry macular degeneration, if applied early enough.

This is a very limited ‘safety study’, to ensure that the treatment does not lead to tumours or other adverse reactions over the next five years. The patients received the transplants more than two years ago with no ill effects, he says.

The next step is to recruit eight people for a similar, but larger, trial. Beyond that, the team is looking to develop treatments for the other layers.

‘We have many of the neural cells we’d like to transplant – as well as some of the blood vessels – but would need sophisticated engineering work to be able to transplant these cells,’ he says. ‘We might finally be able to offer a treatment to everybody once we solve the problem of replacing the other layers.’

Robotic help
Engineering researchers at King’s College London are working to make this transplantation procedure far more delicate and accurate. They are developing a micro-surgical robot that would extend da Cruz’s treatment to layers of the macula that are currently too difficult to reach by manual surgery alone.

‘It’s hard to target these other layers by hand, as it requires much higher precision,’ says Christos Bergeles, associate professor in the Robotics and Vision in Medicine Lab at King’s College.

Bergeles and colleagues are developing a robot – and necessary software – that will help surgeons target these layers. There are two general approaches to robotic surgery: one is called collaborative manipulation or co-manipulation, where the robot extends a surgeon’s natural practice, and is effectively an extension of the scalpel; the second, called tele-manipulation, takes a new approach, where the surgeon sits at a console and uses a joystick or similar device to control the instrument.

‘Surgeons prefer co-manipulation because they retain their position,’ says Bergeles. ‘However, the advantage of tele-manipulation is that it’s simpler to implement.’

He describes the latest version of the robot as a ‘flexible snake’ that works at the back of the eye.

‘It’s a bit unconventional compared to current surgery – and would be tele-manipulated,’ he says.

During the Macular Society’s recent annual conference, the researchers used virtual reality glasses to demonstrate how the system might work. The research is supported by a three-year grant from the National Institute of Health Research (NIHR) in the UK and is half way to completion. By the end of this time, the team intends to have a system ready as a benchtop demonstrator.

‘If we can prove the concept in this way, we will know what we need to do to improve it,’ he says. ‘The main challenge is to achieve the right precision,’ he says.

At the same time, any system for use with humans will need to meet many safety considerations, such as having close control over the operating speed of the ‘scalpel’. It could take five years before a full version of the robot is ready, he says.

Macular degeneration is a widespread, debilitating condition that robs people – mainly the elderly – of their sight. However, the huge body of research into treating it could soon see the end of painful injections – as well as a treatment for the dry form of the disease.