̽��ֱ�� of Cambridge - sight

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

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Power to the people?

bjb42 — Wed, 26 May 2010 08:06:04 +0000

Imagine the following situation, which may be familiar: ̽��ֱ��United States is edging towards armed conflict with an Islamic dictatorship which, it claims, is harbouring powerful weapons of mass destruction. In Britain, the Government vows to stand shoulder to shoulder with its American ally, but there is widespread protest from the voting public. As the deadline for invasion looms, the voice of the people seems to be falling on deaf ears. ̽��ֱ��country, apparently against the majority will, teeters on the brink of war.

Now imagine that this particular version of Britain has also recently undergone radical democratic reform. Thanks to the miracle of the new “e-democracy” website, any eligible citizen can have their say on the issues of the moment and the Government must abide by the wishes of the majority. On an appointed date, you log in and, along with millions of others, cast your vote on whether this war should happen. ̽��ֱ��result is a resounding “no”. British forces are stood down.

Cloud cuckoo land? Science fiction? We forget that in democracy’s cradle of Ancient Greece, the principles at play here would have been utterly recognisable. In Athens, the most famous and radical of the Greek democracies, such issues were decided by an “ekklesia”, or assembly, comprising every eligible member of the voting public. As in the imagined e-democracy, each vote cast counted for one and decision was by majority.

So if Athens, the original democracy, was so different to our own (real) system, have we, in Britain, really come to terms with what democracy means? It’s the sort of question that has clearly been bothering plenty of people since the recent General Election prompted calls for an overhaul of our allegedly “undemocratic” and “broken” electoral process. It is also a theme central to Professor Paul Cartledge’s lecture at the Hay Festival on June 3^rd.

Cartledge is A G Leventis Professor of Greek culture at the ̽��ֱ�� of Cambridge and has written a multitude of books and articles on Ancient Greece and its political thought and practice, along with many other themes. Where politicians frequently invoke democracy’s name because of its potency as an ancient, almost hallowed principle, he is at pains to point out that the Greek interpretation was radically different to our own.

“ ̽��ֱ��only real continuity between ancient and modern democracy is the name,” Cartledge points out. “In fact, the two ideas are so distinctive that it has become a real question for historians of later periods as to why democracy was chosen as the name for this new, representative system that we have now.”

̽��ֱ��Athenian ekklesia is probably the most stark example of this lack of continuity, but there are many others. Ancient Athens had no political parties, no government and no opposition. Even the body of officials which set the ekklesia’s agenda was chosen by random lottery, in which any eligible citizen (this meant male citizens who were “of age”) was potentially electable.

“An ordinary guy could get appointed to a pretty senior governmental position, or find himself as a juror in a crucial state trial,” Cartledge says. “There were some exceptions, but the Athenians were radical. They made the lottery a major political act.”

All of this certainly sounds completely alien compared with our own system. ̽��ֱ��fact is, however, that democracy has always defied clear definition. Taken literally, the term is an amalgam of two Greek words – “demos”, meaning people, and “kratos”, meaning power, but nobody has ever really been able to agree on what the ensuing “people power” should mean.

̽��ֱ��Lincolnian definition, for instance, was government of the People by the People for the People. Leninists, on the other hand, regarded it as meaning the triumph of the proletariat over a ruling elite. For a long time after the demise of the Athenian version, the term was even associable with mob rule. In 6^th century (AD) Byzantium, the word “democracy” meant a riot.

In short, when it comes to the precise meaning of democracy, the jury (however it has been elected) is very much still out. None of which has stopped modern politicians, from the leaders of our newly-installed Coalition to successive leaders of the free world, from identifying it as a symbol of human civilisation that has echoed down through the centuries thanks to the Athenian example.

Cartledge reckons that there are two reasons for this. First, the sheer audacity of Ancient Greece’s radicalism is striking even now, particularly when one considers that until then, any state system had imposed a sharp division between the masses and the ruling elite.

Secondly, Athenian democracy in particular is culturally seductive, because it coincides with some of humanity’s greatest achievements. “ ̽��ֱ��Parthenon, Pericles, Socrates, Sophocles, Plato, Aristotle… one can go on,” Cartledge says. “It’s a bit like Renaissance Florence. There was an extraordinary flowering of culture and that includes political theory.” Never mind that some of the key theorists, like Aristotle, were vehemently opposed to democracy because of its unsavoury, mob connotations.

You could argue that if our own system is indeed both different and “broken”, modern politicians could do worse than look to the Athenians for a few ideas to help them patch it up. ̽��ֱ��growing accessibility of the internet means that “e-democracy”, for example, however space-age it may sound, is increasingly feasible.

This might seem very attractive if we just imagine ourselves voting against war with Iraq. If we think of the same system applied to a nationwide vote on immigration, Europe, or the reinstatement of capital punishment, however, it becomes clear that it is more volatile than we might at first presume.

In fact, a huge gulf between us and the Ancient Athenians prohibits such acts of simple transmutation. “Their governmental system worked because it was direct and face-to-face,” Cartledge says. “ ̽��ֱ��Greeks had tiny communities of a few hundred or a few thousand; not millions.”

“One lesson you learn from Ancient Greece is that it’s not just a matter of technique but a matter of culture. For democracy to work in that form, you had to live it and understand the nuances of the different positions and issues at stake. Nowadays, for very good reasons, we privilege the world of work, or our private lives, over and above politics. It’s very difficult to be democratic.”

So why study the Greek model at all? For Cartledge, the ongoing fascination of Greek democracy is not in its role as a model for our own time, but, more subtly, the set of principles it represents.

“ ̽��ֱ��fundamental principle is a notion of equality,” he explains. “We might not be able to translate the techniques, but we can translate the ideas. What the Greeks show us is that democracy involves creating institutions that most do justice to treating every person’s contribution as politically equal.”

Using Athens as a highly distinctive point of reference helps us to ask important questions about how well our own process is representing the notion of “people power”. Some of these questions are being asked of our electoral system right now. A referendum on alternative voting certainly involves the application of one citizen, one vote, for example, but it could be argued that proportional representation would be truer still to the egalitarian principles at stake.

Cartledge believes that the lottery system used to elect officials could also be “creatively employed” in a modern context, perhaps when it comes to allocating government funds in certain cases, or the selection of an upper house. Recalling the way in which Tony Blair dealt with the invasion of Iraq in 2003, he even, (half) jokingly, wonders whether a system of selective ostracism – the Athenian process whereby a citizen who had made bad political calls could be dismissed, harmlessly, from the political community by popular vote – might work on the odd occasion.

Broadly, however, it is for lessons, ideas and warnings that we should look to the Athenians, rather than systems that we can simply plunder and claim as our own. Whether or not we ultimately go down the route of more referendum politics or dramatically change the way we vote, the merits and drawbacks of these approaches were debated ad nauseam in the Athenian assembly.

“We can’t take over Athenian democracy lock, stock and barrel, but we can use it to inform and change our perception both of their system and our own,” Cartledge adds. “They helps us to see what underlies the notions of ‘the people’, political empowerment and equality. We tend to lose sight of those ideas, because our own world is much more complex. Understandably, that means that in our own time, there is perhaps more reluctance to empower ordinary citizens than there was in Ancient Athens.”

Paul Cartledge will be speaking at the Hay Festival on June 3^rd, at 10.30am.

Greece was the birthplace of democracy, but our own political system would be unrecognisable to voters in Ancient Athens. As Classicist Paul Cartledge explains, however, that doesn’t mean that our ancient forbears have left us with nothing to learn.

We can’t take over Athenian democracy lock, stock and barrel, but we can use it to inform and change our perception both of their system and our own

Dr Paul Cartledge

D'Arcy Norman from Flickr

Democracy

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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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An invention to help the ageing eye

amb206 — Sat, 01 Sep 2007 00:00:00 +0000

Progressive loss in accommodative power by the lens of the human eye – a condition known as presbyopia – affects almost everybody who enters middle age and interferes with their ability to focus on close objects. As we live longer and continue to pursue challenging visual activities, the demand for presbyopic correction is increasing.

̽��ֱ��effects of presbyopia are particularly felt by regular computer users – the screen lies at a middle distance, which varies as the subject’s posture alters and is rarely catered for by current presbyopic spectacles. Until now, the solution has been to use bifocal or varifocal lenses, but these offer limited fields of view at various fixed distances. Instead, the ideal presbyopic correction should provide a full field of vision with clear focus for any distance between infinity and the near point – and this is what has been accomplished by Dr Paul Meyer, in the Department of Ophthalmology, Addenbrooke’s Hospital, Cambridge.

Developed in conjunction with NHS clinical engineers, the technology gives users a wide field of view with no distortion and high resolution at any distance. ̽��ֱ��new lenses are based on the simple optical principle that the air gap between a pair of nesting concave and convex lenses develops increasing positive power as it widens. A compact, low-friction movement above the bridge of the nose allows the wearer to focus easily using a single roller situated on either side of the frame. Dr Meyer is commercialising the technology through Cambridge Enterprise Ltd, who are looking for licensing partners or investors.

For more information, please contact Dr Iain Thomas (iain.thomas@enterprise.cam.ac.uk; Tel: 01223 760339) at Cambridge Enterprise Ltd.

Progressive loss in accommodative power by the lens of the human eye &ndash; a condition known as presbyopia &ndash; affects almost everybody who enters middle age and interferes with their ability to focus on close objects. As we live longer and continue to pursue challenging visual activities, the demand for presbyopic correction is increasing.

Baron Brian from flickr

Eye

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Parasites: the master manipulators

tdk25 — Sat, 01 Sep 2007 00:00:00 +0000

̽��ֱ��human race used to have a consensus attitude towards the organisms that we call parasites. They were simply pests, causative agents of disease that warranted nothing else other than extermination. As soon as new life-cycles were described in the literature, the race began to find a way of interrupting transmission and end the misery. ̽��ֱ��literature is therefore full of examples of control programmes for just about every parasite that has ever been identified. Some, such as the programme against the guinea worm, Dracunculus medinensis, have been so successful that complete eradication is now on the World Health Organization’s agenda.

As we wave goodbye to the guinea worm, it will be time to re-visit the hit-list, and to see how far we’ve progressed. In doing so, we are likely to observe that not much has changed. In fact, the guinea worm is the only parasitic infection that has ever been described and then systematically eradicated. There are even signs that the parasitic fauna of the planet is flourishing – recent estimates put the toll of malaria at between 300 and 660 million cases a year, and there are still hundreds of millions of people infected by each of several parasitic worm species. This group includes the trematode parasite Schistosoma mansoni – a blood fluke that infects approximately 200 million people in the tropics and sub-tropics, and which has been the focus of research efforts at the ̽��ֱ�� of Cambridge Department of Pathology for the past 30 years.

Fighting the fluke

Theodor Bilharz formally described schistosome parasites in 1851, at which point the centimetre-long, red-blood-cell-eating worm joined the most-wanted list. Like every other parasitic infection, S. mansoni was viewed with fear and loathing – and with good reason. Infection occurs through contact with free-living larvae in freshwater, with rapid penetration of intact human skin. ̽��ֱ��adults live in the mesenteric veins between the liver and gut. Females produce eggs that become trapped in the liver, promoting an inflammatory response that eventually leads to a form of hepatic fibrosis and portal hypertension. About half the eggs pass through the gut wall, each puncture causing a small amount of blood to be lost. As the worm burden increases with repeated exposure, so the number of eggs in both the liver and gut increases, leading to ever more severe disease.

Early attempts at large-scale control of schistosome infections relied on crude drugs and environmental modification, with success in some areas, but in most places the parasite persisted. Although treatment (praziquantel) is available, re-infection occurs rapidly, especially in children. ̽��ֱ��lack of effective, non-toxic medicine, and the success of vaccination programmes against bacterial diseases, led to the emergence of renewed research efforts aimed at understanding the biology of the worm and its relationship with the human host.

But, despite promises of an anti-schistosome vaccine ‘within five years’ for the past 20 years or so, there is still no vaccine available, because we don’t yet understand the biology of the schistosome worm. Like a fractal puzzle, as we peer more closely we see even greater complexity.

Keeping things quiet

Such is the intimate relationship between host and parasite that we can use the study of schistosome parasites to understand how humans work. One of the key questions that has kept scientists busy is how schistosomes manage to evade the immune response for extended periods. It has been estimated that adult worms live for up to 10 years in their human host. To make this possible, the worms have evolved several mechanisms for diverting, blocking and repressing the immune response. ̽��ֱ��adult worms coat themselves in host proteins to appear invisible to the immune system. They induce the host to produce ineffective immune responses and they manipulate host cells to produce molecules that signal a general downregulation of the host’s response. This essentially produces a drowsy immune response with impaired vision against a camouflaged target – perfect conditions for the parasite to thrive and reproduce

Recent studies in Cambridge in the laboratory of Professor David Dunne have demonstrated the magnitude of this repressive effect by treating people who are already infected with the parasite and measuring their immune responses before and after taking praziquantel. Responses that are thought to be effective against the parasite often increase several fold after drug treatment, and this ‘boosting’ of the host’s ability to respond appears to help prevent re-infection in the future. Recently, the scientists also reported that the ability to respond after treatment is genetically restricted – an observation that has important implications for the development of any therapy or vaccine that relies on increasing the magnitude of the immune response for its protective effect.

Medical benefits

Although a vaccine is not yet in sight, recent discoveries have raised an interesting conundrum: rather than simply being agents of disease, it appears that parasitic infections, including schistosome worms, may bring medical benefits. Scientists in Cambridge are leading the field in efforts to find out just what is going on.

As more knowledge of the host–parasite relationship is gained, it is becoming increasingly clear that parasitic infections are not necessarily pests that need to be eradicated. Nobody used to have any sympathy for leeches or maggots, but both creatures are now used in medical settings: leeches to clear blood from congested tissues after surgery, and maggots to liquefy dead tissue and kill harmful bacteria in infected wounds. ̽��ֱ��same thing is now happening to parasites, as it emerges that their influence on the immune system can benefit both host and parasite.

In the Department of Pathology, a clear example of this win–win scenario was demonstrated when researchers in Professor Anne Cooke’s group prevented type 1 diabetes from developing in mice by injecting them with antigens of schistosome parasites. This is likely to be due to the same skewing and downregulation of the host immune response described above.

It seems that by diverting and subverting the immune response, schistosome parasites may prevent the immune system from over-reacting to other proteins. One hypothesis gaining popularity is that, when parasites are removed, the immune response finds new targets, either in harmless allergens (leading to allergy), or in the host itself (leading to autoimmune diseases such as type 1 diabetes).

With such tantalising evidence, it may be time to look at the parasite hit-list with fresh eyes, and ask: can we exploit the intimate relationship parasites have with humans at the same time as reducing their tremendous burden on affected populations?

̽��ֱ��Matangini Project

̽��ֱ��Matangini Project was created by Dr Mark Booth, in the Schistosomiasis Research Group at the Department of Pathology, to raise funds for community projects in Kenya and Uganda. ̽��ֱ��aim in 2007 is to raise £5000 to bring safe water to thousands of school children in areas of Kenya affected alternately by drought and water-borne infections such as schistosomiasis.

Cambridge Infectious Disease Initiative

̽��ֱ�� ̽��ֱ�� of Cambridge is currently developing a major Infectious Disease Initiative, with the aim of increasing the ̽��ֱ��’s contribution to reducing the global impact of infectious diseases. By building new partnerships based on core strengths, the vision is to establish the ̽��ֱ�� as a leading international centre for infectious disease teaching and research.

For further information, please contact the Co-ordinator Dr Gill Rands (gfr21@cam.ac.uk).

For more information, please contact the author Dr Mark Booth (mb350@cam.ac.uk) at the Department of Pathology (www.path.cam.ac.uk/~schisto).

̽��ֱ��common view has been that parasitic infections cause disease and must be eliminated. But can we live without them?

As more knowledge of the host–parasite relationship is gained, it is becoming increasingly clear that parasitic infections are not necessarily pests that need to be eradicated.

Max0rz from Flickr

Flatworm

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