̽��ֱ�� of Cambridge - eyesight

Gene therapy injection in one eye surprises scientists by improving vision in both

ta385 — Thu, 10 Dec 2020 06:00:00 +0000

In a landmark phase 3 clinical trial, the international team, coordinated by Dr Patrick Yu-Wai-Man from the ̽��ֱ�� of Cambridge and Dr José-Alain Sahel from the ̽��ֱ�� of Pittsburgh and Institut de la Vision, Paris, successfully treated 37 patients suffering from Leber hereditary optic neuropathy (LHON). Subject to further trials, the treatment could help thousands of people across the world to regain and retain some of their sight.

̽��ֱ��study, published today in the journal Science Translational Medicine, indicates that 78% of treated patients experienced significant visual improvement in both eyes. It suggests that the improvement in vision in untreated eyes could be due to the transfer of viral vector DNA from the injected eye.

LHON affects a specific type of retinal cells, known as retinal ganglion cells, causing optic nerve degeneration and rapidly worsening vision in both eyes. Within a few weeks of disease onset, the vision of most people affected deteriorates to levels at which they are considered legally blind. Visual recovery occurs in less than 20% of cases and few achieve vision better than 20/200 (largest letter on a standard eye chart). LHON affects approximately 1 in 30,000 people, mostly men, with symptoms usually emerging in their 20s and 30s. ̽��ֱ��majority of patients carry the m.11778G>A mutation in the MT-ND4 gene. Existing treatment for this blinding optic neuropathy remains limited.

“As someone who treats these young patients, I get very frustrated about the lack of effective therapies,” said senior investigator Dr Sahel, a professor of ophthalmology at the ̽��ֱ�� of Pittsburgh. “These patients rapidly lose vision in the course of a few weeks to a couple of months. Our study provides a big hope for treating this blinding disease in young adults.”

̽��ֱ��researchers injected rAAV2/2-ND4 – a viral vector containing modified cDNA – into the vitreous cavity at the back of one eye of 37 patients who had suffered vision loss for between 6 to 12 months. Their other eye received a sham injection. ̽��ֱ��technology, called mitochondrial targeting, was developed by the Institut de la Vision in Paris, France, and licensed to GenSight Biologics.

International coordinating investigator and neuro-ophthalmologist Dr Yu-Wai-Man, from Cambridge’s Department of Clinical Neurosciences and Moorfields Eye Hospital, London, said: “We expected vision to improve in the eyes treated with the gene therapy vector only. Rather unexpectedly, both eyes improved for 78% of patients in the trial following the same trajectory over 2 years of follow-up.”

Treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of 15 letters on an ETDRS chart, representing three lines of vision, while a mean improvement of 13 letters was observed in the sham treated eyes. As some patients were still in the dynamic phase of the disease process upon enrolment, the visual gain from the nadir (worst BCVA for each eye) was even larger, reaching 28.5 letters for the treated eyes and 24.5 letters for sham-treated eyes.

Dr Yu-Wai-Man said: “By replacing the defective MT-ND4 gene, this treatment rescues the retinal ganglion cells from the destructive effects of the m.11778G>A mutation, preserving function and improving the patient’s visual prognosis. ̽��ֱ��outcomes can be life-changing.”

̽��ֱ��researchers found that treated eyes were around three times more likely to achieve vision better than or equal to 20/200. Patient-reported outcome measures evaluated using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) also confirmed the positive impact of treatment on quality of life and psychosocial well-being.

̽��ֱ��researchers then conducted a study in cynomolgus macaques to investigate how the treatment of one eye could bring about improvement in the other. Macaques have a visual system similar to that of humans, which allows the distribution and effects of the gene therapy vector to be studied in much greater detail. A unilateral injection of rAAV2/2-ND4 was administered and after three months, tissues from various parts of the eye and the brain were analysed to detect and quantify the presence of viral vector DNA using a transgene-specific quantitative PCR assay.

Viral vector DNA was detected in the anterior segment, retina and optic nerve of the untreated eye. ̽��ֱ��unexpected visual improvement observed in the untreated eyes could therefore reflect the interocular diffusion of rAAV2/2-ND4. Further investigations are needed to confirm these findings and whether other mechanisms are contributing to this bilateral improvement.

Dr Yu-Wai-Man said: “Saving sight with gene therapy is now a reality. ̽��ֱ��treatment has been shown to be safe and we are currently exploring the optimal therapeutic window.”

“Our approach isn’t just limited to vision restoration,” added Dr Sahel. “Other mitochondrial diseases could be treated using the same technology.”

Notes

rAAV2/2-ND4 (GS010) is a recombinant replication-defective adeno-associated virus, serotype 2, which contains a modified cDNA encoding the human wild-type mitochondrial ND4 protein and a specific mitochondrial targeting sequence (MTS) for directing the protein to the mitochondrial compartment.

The ETDRS chart consists of rows of 5 letters each and it is used to measure visual acuity.

Funding

̽��ֱ��study was fully funded and sponsored by GenSight Biologics.

Reference

Patrick Yu-Wai-Man et al., 'Bilateral Visual Improvement with Unilateral Gene Therapy Injection for Leber Hereditary Optic Neuropathy'; Science Translational Medicine (9 December 2020). DOI: 10.1126/scitranslmed.aaz7423

Injecting a gene therapy vector into one eye of someone suffering from LHON, the most common cause of mitochondrial blindness, significantly improves vision in both eyes, scientists have found.

Saving sight with gene therapy is now a reality

Patrick Yu-Wai-Man

Phoenix Thomas via Pixabay

A young man's eye. Image by Phoenix Thomas via Pixabay

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Technique to regenerate the optic nerve offers hope for future glaucoma treatment

cjb250 — Thu, 05 Nov 2020 10:00:30 +0000

Axons – nerve fibres – in the adult central nervous system (CNS) do not normally regenerate after injury and disease, meaning that damage is often irreversible. However, over the past decade there have been a number of discoveries that suggest it may be possible to stimulate regeneration.

In a study published today in Nature Communications, scientists tested whether the gene responsible for the production of a protein known as Protrudin could stimulate the regeneration of nerve cells and protect them from cell death after an injury.

̽��ֱ��team, led by Dr Richard Eva, Professor Keith Martin and Professor James Fawcett from the John van Geest Centre for Brain Repair at the ̽��ֱ�� of Cambridge, used a cell culture system to grow brain cells in a dish. They then injured their axons using a laser and analysed the response to this injury using live-cell microscopy. ̽��ֱ��researchers found that increasing the amount or activity of Protrudin in these nerve cells vastly increased their ability to regenerate.

Nerve cells in the retina, known as retinal ganglion cells, extend their axons from the eye to the brain through the optic nerve in order to relay and process visual information. To investigate whether Protrudin might stimulate repair in the injured CNS in an intact organism, the researchers used a gene therapy technique to increase the amount and activity of Protrudin in the eye and optic nerve. When they measured the amount of regeneration a few weeks after a crush injury to the optic nerve, the team found that Protrudin had enabled the axons to regenerate over large distances. They also found that the retinal ganglion cells were protected from cell death.

̽��ֱ��researchers showed that this technique may help protect against glaucoma, a common eye condition. In glaucoma, the optic nerve that connects the eye to the brain is progressively damaged, often in association with elevated pressure inside the eye. If not diagnosed early enough, glaucoma can lead to loss of vision. In the UK, round one in 50 people over the age of 40, and one in ten people over the age of 75 is affected by glaucoma.

To demonstrate this protective effect of Protrudin against glaucoma, the researchers used a whole retina from a mouse eye and grew it in a cell-culture dish. Usually around a half of retinal neurons die within three days of retinal removal, but the researchers found that increasing or activating Protrudin led to almost complete protection of retinal neurons.

Dr Veselina Petrova from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author, said: “Glaucoma is one of leading causes of blindness worldwide. ̽��ֱ��causes of glaucoma are not completely understood, but there is currently a large focus on identifying new treatments by preventing nerve cells in the retina from dying, as well as trying to repair vision loss through the regeneration of diseased axons through the optic nerve.

“Our strategy relies on using gene therapy – an approach already in clinical use – to deliver Protrudin into the eye. It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow. It’s important to point out that these findings would need further research to see if they could be developed into effective treatments for humans.”

Protrudin normally resides within the endoplasmic reticulum, tiny structures within our cells. In this study, the team showed that the endoplasmic reticulum found in axons appears to provide materials and other cellular structures important for growth and survival in order to support the process of regeneration after injury. Protrudin stimulates transport of these materials to the site of injury.

Dr Petrova added: “Nerve cells in the central nervous system lose the ability to regenerate their axons as they mature, so have very limited capacity for regrowth. This means that injuries to the brain, spinal cord and optic nerve have life-altering consequences.

“ ̽��ֱ��optic nerve injury model is often used to investigate new treatments for stimulating CNS axon regeneration, and treatments identified this way often show promise in the injured spinal cord. It’s possible that increased or activated Protrudin might be used to boost regeneration in the injured spinal cord.”

̽��ֱ��research was supported by the Medical Research Council, Fight for Sight, the Bill and Melinda Gates Foundation, Cambridge Eye Trust and the National Eye Research Council.

Reference
Petrova, V et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Comms; 5 Nov 2020; DOI: 10.1038/s41467-020-19436-y

Scientists have used gene therapy to regenerate damaged nerve fibres in the eye, in a discovery that could aid the development of new treatments for glaucoma, one of the leading causes of blindness worldwide.

It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow

Veselina Petrova

TobiasD

Eye

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Killer flies: how brain size affects hunting strategy in the insect world

sc604 — Tue, 09 Feb 2016 09:10:36 +0000

As in economics, there is a law of diminishing returns in neuroscience – doubling the investment going in doesn’t equal double the performance coming out. With a bigger brain comes more available resources that can be allocated to certain tasks, but everything has a cost, and evolution weighs the costs against the benefits in order to make the most efficient system.

“Larger brains are specialised for high performance, so there’s a definite advantage to being bigger and better,” says Professor Simon Laughlin of the Department of Zoology, whose research looks at the cellular costs associated with various neural tasks. “But since most animals actually have very small brains, there must also be advantages to being small.” Indeed, there is strong selection pressure to have the minimum performance required in order to survive and it’s not biologically necessary to be the best, only to be better than the nearest competitor.

So does size matter? Do small insects with relatively few neurons have the same capabilities as much larger animals? “When an animal is limited, is it because their neural system just can’t cope? Or is it because they’re actually optimised for their particular environment?” asks Dr Paloma Gonzalez-Bellido from Cambridge’s Department of Physiology, Development and Neuroscience.

With funding from the US Air Force, Gonzalez-Bellido is studying the hunting behaviours of various flying insects – from tiny killer flies, slightly larger robber flies to large dragonflies – to determine how their visual systems influence their attack strategy, and what sorts of trade-offs they have to make in order to be successful.

Dragonflies are among the largest flying insects, and hunt smaller insects such as mosquitoes while patrolling their territories. They have changed remarkably little in the 300 million years since they evolved – most likely because they are so well optimised for their particular environmental niche.

“Other researchers have found that dragonflies are capable of doing complex things like internally predicting what their body is going to do and compensating for that – for instance, if they’re chasing a target and turn their wings, another signal will be sent to turn their head, so that the target stays in the same spot in their visual field,” says Gonzalez-Bellido. “But are smaller animals, such as tiny flies, capable of achieving similarly complex and accurate feats?”

Gonzalez-Bellido also studies the killer fly, or Coenosia attenuata. These quick and ruthless flies are about four millimetres long, and will go after anything they think they can catch – picky eaters they are not. However, the decision to go after their next meal is not as simple as taking off after whatever tasty-looking morsels happen to fly by. As soon as a killer fly takes off after its potential prey, it exposes itself and runs the risk of becoming a meal for another killer fly.

To help these predacious and cannibalistic flies eat (and prevent them from being eaten), they need to fly fast and to see fast. Insects see at speeds much higher than most other animals, but even for insects, killer flies and dragonflies see incredibly fast, at rates as high as 360 hertz (Hz) – as a comparison, humans see at around 60 Hz.

“For prey animals, the most important thing is to get out of the way quickly – it doesn’t matter whether they know exactly what’s coming, just that it doesn’t catch them,” says Gonzalez-Bellido. “Predators need to be both fast and accurate in their movements if they’re going to be successful – but for very small predators such as insects, there are trade-offs that need to be made.”

By making the ‘pixels’ on their photoreceptors (the light-sensitive cells in the retina) as narrow as possible, killer flies trade sensitivity for resolution. In bright light, they see better than their similar-sized prey, the common fruit fly. However, the cap on sensitivity and resolution imposed upon killer flies by their tiny eyes means that they can only see and attack things that fly close by.

While dragonflies, with their larger eyes and better resolution, can take their time and use their brain power to calculate whether a prey is suitable for an attack, killer flies attack before they’ve had a chance to determine whether it’s something they can actually catch, subdue or eat – or they risk missing their prey altogether. Once a killer fly gets relatively close to its potential prey, it has to decide whether to keep going or turn back – this is one of the trade-offs resulting from evolving such a tiny visual system.

In the early 2000s, Laughlin determined the energy efficiency of single neurons, by estimating the numbers of ATP molecules – the molecules that deliver energy in cells – used per bit of information coded. To do this he compared photoreceptors in various insects. Laughlin and his colleagues found that photoreceptors are like cars – the higher the performance, the more energy they require, and costs rise out of proportion with performance. “For any system, whether it’s in a tiny insect or a large mammal, you don’t want something which is over-engineered, because it’s going to cost more,” says Laughlin. “So what’s the root of inefficiency, and how did nature evolve efficient nerve cells from the bottom up?”

Researchers in the Department of Engineering are taking the reverse approach to answer questions about how the brain works so efficiently by looking at systems from the top down. “If you reverse engineer an animal’s behavioural strategy by asking how an animal would solve a task under specific constraints and then work out the optimal solution, you’ll find it’s often the case that animals are pretty close to optimal,” says Dr Guillaume Hennequin, who looks at how neurons work together to produce behaviour.

Hennequin studies how brain circuits are wired in such a way that they become optimised for a task: how primates such as monkeys are able to estimate the direction of a moving object, for example. “How brain circuits generate optimal interpretations of ambiguous information received from imperfect sensors is still not known,” he says. “Coping with uncertainty is one of the core challenges that brains must confront.”

Different animals come up with their own solutions. Both dragonflies and killer flies have systems that are optimal, but optimal in their own ways. It’s beneficial for killer flies to be so small, since this gives them high manoeuvrability, enabling them to catch prey that turns at speed. Dragonflies are much bigger, and can do things that killer flies can’t, but their size means they can’t turn or stop on a dime, like a killer fly can.

“By answering some of the questions around efficiency in brain circuits, large or small, we may be able to understand fundamental principles about how brains work and how they evolved,” says Laughlin.

Inset images: top to bottom: robber fly, dragon fly, killer fly; credit: Sam Fabian.

Cambridge researchers are studying what makes a brain efficient and how that affects behaviour in insects.

When an animal is limited, is it because their neural system just can’t cope? Or is it because they’re actually optimised for their particular environment?

Paloma Gonzalez-Bellido

Sam Fabian

Size comparison of robber fly, dragon fly, killer fly (left to right)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Researchers develop new test for children with vision loss

sjr81 — Tue, 11 Oct 2011 15:47:27 +0000

Dr Louise Allen, a paediatric ophthalmologist at the ̽��ֱ�� of Cambridge, and Dr Adar Pelah, an electronics engineer at the ̽��ֱ�� of York, have developed a specialised visual field test system to detect peripheral vision defects, called KidzEyez.

Peripheral visual field loss in children can result from prematurity, eye disorders such as retinal dystrophy, brain conditions such as cerebral palsy, neurosurgery, drug therapy, or brain tumours.

Most children with brain tumours will develop visual field loss due to the tumour’s interference with the visual pathway, which stretches from the optic nerve at the very front of the brain to the visual cortex at the back of the brain. Unfortunately, visual field loss in young children is currently very difficult to assess; timely recognition could lead to earlier diagnosis and treatment of its cause, resulting in the prevention of severe visual impairment, improved outcomes and more individualised support.

Current techniques for measuring the peripheral visual field require the subject to sit still and maintain a steady gaze at a light target for as long as ten minutes. These tests can be difficult enough for an adult to perform, let alone a young child.

̽��ֱ��clinical need for a perimeter suitable for use in young children led Dr Allen and Dr Pelah to develop a system which is child-friendly, fast, but accurate in detecting peripheral visual field loss.

Using the KidzEyez system, the child watches a central cartoon on a video screen, while their natural looking response to a target appearing in different locations of the visual periphery is monitored remotely using a small camera located on the video screen. If the target falls within the intact visual field, the child will reflexively look at the target; if the target falls within a blind area, no response will be seen.

“KidzEyez is the first perimeter specifically designed for young children,” said Dr Allen. “Children find the testing fun and, by improving our detection and management of visual pathway tumours, KidzEyez could play a major role in preserving sight and improving our support of children with visual impairment.”

A trial of the KidzEyez perimeter at Addenbrooke’s Hospital, Cambridge has recently been completed on 74 children between three and 10 years of age, some with and some without predicted visual field loss. ̽��ֱ��results were compared with currently available confrontation testing, which involves the examination of the child’s response to a small toy held in their visual periphery. KidzEyez was found to have 100% sensitivity and specificity compared to confrontation testing but, importantly, gave an interpretable result in more than 70% of children whose concentration was too poor for confrontation testing.

Dr Allen will present the findings of the study at the conference of the British Isles Paediatric Ophthalmology and Strabismus Association this week in London.

KidzEyez has been funded by Cambridge Enterprise, the ̽��ֱ��’s commercialisation group, and the ̽��ֱ�� of York. Cambridge Enterprise is currently seeking commercial partners for licensing, collaboration and development of this technology.

Technology developed at the ̽��ֱ�� of Cambridge to detect peripheral visual field loss in young children will enable the earlier detection of brain tumours, potentially saving sight and lives.

KidzEyez is the first perimeter specifically designed for young children.

Louise Allen

Cambridge Enterprise

Dr Louise Allen

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Guiding the light

ns480 — Sat, 01 Sep 2007 13:40:33 +0000

Incredibly sophisticated in structure and function, the retina's construction has puzzled researchers ever since the finer structures of the eye were first resolved over 150 years ago: the retina is built the ‘wrong’ way around. ̽��ֱ��cells responsible for light sensing are sited at the back of the eye, furthest from the incoming light. An explanation for the ‘inverted retina’ has now been revealed by Dr Jochen Guck, newly arrived at the Cavendish Laboratory, while working with a team of scientists at the ̽��ֱ�� of Leipzig, Germany.

Because of its inverted structure, light has to pass through several cells in the retina before it reaches the photoreceptor cells that capture the image and transmit it to the brain. How does this happen without the light being scattered and distorted? Dr Guck describes the problem: ‘Nobody would put sandwich paper in their camera in front of the film and expect a crisp image – like the one we’re used to seeing. And yet, this is how the retina is constructed.’

An understanding of this enigma has become possible with the invention of a special dual-beam laser trap or ‘Optical Stretcher’ by Dr Guck and colleagues, in which physical, light-transmitting properties can be visualised and measured at the level of a single cell. Using this tool, the researchers discovered that the answer to the mystery lies with specialised, elongated cells known as Müller cells, which span the retina and have an amazingly high refractive index compared with their surroundings. This difference in refractive index effectively means the light ‘bounces’ along the cell and barely leaks.

̽��ֱ��ground-breaking studies, highlighted on the front cover of the Proceedings of the National Academy of Sciences USA, showed that the Müller cells essentially act as a field of miniature optic fibres – lined up in parallel in the direction of the light and traversing the whole retina. They trap the light, guide it down their length, and deliver it to the photoreceptors waiting to receive the stimulus. ‘All these living optical fibres together work like a fibreoptic plate,’ says Dr Guck.

With his move to the Cavendish Laboratory, Dr Guck has brought with him the new expertise of using light to investigate the mechanical and optical properties of living cells and tissues. His research adds to an ongoing initiative within the ̽��ֱ�� to draw physics more deeply into the life sciences.

For more information, please contact Dr Jochen Guck (jg473@cam.ac.uk). This research was published in PNAS (2007) 104, 8287–8292.

Pioneering research shines new light on our understanding of the way we see the world. Optical fibres have now been found to exist in vertebrate eyes, channelling light down their length and delivering it without distortion straight to the cells that ‘see’.

Nobody would put sandwich paper in their camera in front of the film and expect a crisp image – like the one we’re used to seeing. And yet, this is how the retina is constructed.

Dr Guck

pasukaru76

Fiber Optics

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