̽��ֱ�� of Cambridge - retina

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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From Mexican wave to retinal wave: why sharing data is good for science

jfp40 — Mon, 07 Apr 2014 10:40:34 +0000

Now, researchers at Cambridge, York, Newcastle and Imperial College London have developed a system allowing neurophysiologists to share raw data with each other, something they hope will generate new discoveries in the field. ̽��ֱ��results are published in the journal GigaScience.

̽��ֱ��first type of data they collected and standardised are recordings of so called ‘retinal waves’. During early development, retinal neurons generate signals that rapidly spread across from one cell to another, much like a Mexican wave in a football stadium. These patterns of activity are thought to help forge the neural connections from the eye to the brain.

To record retinal waves, scientists use multielectrode arrays (tiny electrical devices). In this research, the team took 366 recordings from 12 different studies published between 1993 and 2014, converted them all to HDF5 – a standard open source format – and published them in a web-based ‘virtual laboratory’ called CARMEN.

According to lead author Dr Stephen Eglen from the Cambridge Computational Biology Institute: “Unlike other fields such as genomics, there hasn’t been much public data sharing in neuroscience, which could be because the data are heterogeneous and hard to annotate, or because researchers are reluctant to share data with a competitor.”

But Eglen believes there is much to be gained by a more cooperative approach. “There are two main benefits to sharing,” he said. “As well as leading to other collaborations and more interesting research, it also means that other people can check what you’ve done, which leads to more robust research. And if the taxpayer funds research, then I think it’s important for those results to be publicly available.”

CARMEN was a pilot project funded by the EPSRC, and is now supported by the BBSRC.

From the way we learn, to how our memories are made and stored, the workings of our brains depend on connections forged between billions of neurons, yet much about how our nervous system develops remains a mystery.

There are two main benefits to sharing. As well as leading to other collaborations and more interesting research, it also means that other people can check what you’ve done, which leads to more robust research.

Dr Stephen Eglen

Oyvind Solstad

Eye 9

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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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