Microchip Restores Vision

A wirelessly controlled microchip has restored limited vision to patients in a small experimental trial, report researchers in the Proceedings of the Royal Society B.

The German medical technology company Retina Implant developed the artificial retina, which was implanted in one eye of each participant as part of a company-funded trial. The patients had all been blinded by retinitis pigmentosa or another inherited disease that cause the eye’s light-detecting rod and cone cells, called photoreceptors, to degenerate and die over time. In theory, the device could also benefit patients with degenerative eye diseases such as macular degeneration, says Katarina Štigl, a clinical scientist and ophthalmologist at the University of Tübingen, who led the study.

With the implant, eight of the nine patients in the trial could perceive light. Five were able to detect moving patterns on a screen as well as everyday objects such as cutlery, doorknobs, and telephones. Three were able to read letters. Seeing their own hands and the faces of their loved ones had the biggest impression on the patients, says Štigl. “The very personal things, such as if a mouth is smiling, or the shape of a nose, are the most exciting for them,” she says.

The implanted device consists of a three-millimeter-square chip with 1,500 pixels. Each pixel contains a photodiode, which picks up incoming light, and an electrode and an amplification circuit, which boosts the weak electrical activity given off by the diode. A thin cable that runs through the eye socket connects the implant to a small coil implanted under the skin behind the ear, which means most of the system is invisible. The coil under the skin is powered by an external battery pack that can be held behind the ear with magnets.

The results follow an announcement earlier this week from California-based Second Sight that its Argus II system was approved for use in the United States. The two technologies take different approaches to restoring vision in patients with retinal degeneration. In Second Sight’s system, a camera mounted on eyeglasses picks up images that are converted into electrical signals by a small wearable computer. That data is then sent to a 60-electrode chip to stimulate neurons in the retina. The Retina Implant device instead attempts to directly replace the lost photoreceptors, allowing the remaining retinal circuitry to do the data processing.

Research finds protein that prevents light-induced retinal degeneration

Research led by Minghao Jin, PhD, Assistant Professor of Ophthalmology and Neuroscience at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, has found a protein that protects retinal photoreceptor cells from degeneration caused by light damage. This protein may provide a new therapeutic target for both an inherited retinal degenerative disease and age-related macular degeneration. The paper is published in the February 13, 2013 issue of the Journal of Neuroscience.

The visual cycle is essential for regenerating visual pigments that sense light for vision. However, abnormal visual cycles promote formation of toxic byproducts that contribute to the development of age-related macular degeneration (AMD), the leading cause of vision loss in elderly people that affects an estimated 2 million Americans. The mechanisms that regulate the visual cycle have been unclear. Identification and characterization of regulators of the visual cycle enzymes are critical for understanding these mechanisms.

RPE65 is a key enzyme involved in the visual cycle. RPE65 mutations have been linked to early onset vision loss, retinal degeneration, and blinding eye diseases. Despite such importance, the mechanisms that regulate the function of RPE65 are unknown. To identify and characterize previously unknown inhibitors of RPE65, the scientists tested five candidate proteins. Using gene screening, the LSUHSC research team discovered that one of them – fatty acid transport protein 4 (FATP4) – is a negative regulator; it inhibits RPE65.

"We found that FATP4 protects retinal photoreceptor cells from experimentally-induced retinal degeneration," notes Nicolas Bazan, MD, PhD, Boyd Professor, Ernest C. and Yvette C. Villere Endowed Chair of Retinal Degeneration, and Director of the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, who is a co-author of the paper.

Recently, mutations in the human FATP4 gene have been identified in patients with a certain recessive disorder which also features one of the toxic byproducts associated with abnormal visual cycles. This byproduct, called A2E accumulates in retinal pigment epithelial cells with age, prompting a call for further investigation to determine whether FATP4 mutations cause age-related vision impairment and retinal degeneration.

"These findings suggest that FATP4 may be a therapeutic target for the inherited retinal degenerative disease caused by RPE65 mutations and AMD," concludes Dr. Jin.

(Image: Eyeland Design Network)

Altering eye cells may one day restore vision

Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye, according to scientists at Washington University School of Medicine in St. Louis.

Working in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. The scientists now are conducting additional tests to confirm that the mice can still see.

“We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells,” says senior author Joseph Corbo, MD, PhD, assistant professor of pathology and immunology. “A diseased retina is not a hospitable environment for transplanting stem cells.”

The study is available in the early online edition of Proceedings of the National Academy of Sciences.

Mutations in more than 200 genes have been linked to various forms of blindness. Efforts are underway to develop gene therapies for some of these conditions.

Rather than seek treatments tailored to individual mutations, Corbo hopes to develop therapies that can alleviate many forms of visual impairment. To make that possible, he studies the genetic factors that allow cells in the developing eye to take on the specialized roles necessary for vision.

Study Sheds Light on the Complexity of Gene Therapy for Congenital Blindness

Independent clinical trials, including one conducted at the Scheie Eye Institute at the Perelman School of Medicine, have reported safety and efficacy for Leber congenital amaurosis (LCA), a congenital form of blindness caused by mutations in a gene (RPE65) required for recycling vitamin A in the retina. Inherited retinal degenerative diseases were previously considered untreatable and incurable. There were early improvements in vision observed in the trials, but a key question about the long-term efficacy of gene therapy for curing the retinal degeneration in LCA has remained unanswered. Now, new research from the Scheie Eye Institute, published this week in the Proceedings of the National Academy of Sciences, finds that gene therapy for LCA shows enduring improvement in vision but also advancing degeneration of affected retinal cells, both in LCA patients and animal models of the same condition.

LCA disease from RPE65 mutations has two-components: a biochemical blockade leading to impaired vision, and a progressive loss of the light-sensing photoreceptor cells throughout life of the affected patient. The authors of the new study explain that until now gene therapy has been optimistically assumed, but not proven, to solve both disease components at the same time.

“We all hoped that the gene injections cured both components – re-establishing the cycle of vision and also preventing further loss of cells to the second disease component” said Artur V. Cideciyan, PhD, lead author and co-investigator of an LCA clinical trial at Penn.

Yet, when the otherwise invisible cell layers of the retina were measured by optical imaging in clinical trial participants serially over many years, the rate of cell loss was the same in treated and untreated regions. “In other words, gene therapy improved vision but did not slow or halt the progression of cell loss,” commented Cideciyan.

“These unexpected observations should help to advance the current treatment by making it better and longer lasting,” commented co-author Samuel G. Jacobson, MD, PhD, principal investigator of the clinical trial. “Slowing cell loss in different retinal degenerations has been a major research direction long before the current gene therapy trials. Now, the two directions must converge to ensure the longevity of the beneficial visual effects in this form of LCA.”

(Image: bigstockphoto)

Study of how eye cells become damaged could help prevent blindness

Light-sensing cells in the eye rely on their outer segment to convert light into neural signals that allow us to see. But because of its unique cylindrical shape, the outer segment is prone to breakage, which can cause blindness in humans. A study published by Cell Press on January 22nd in the Biophysical Journal provides new insight into the mechanical properties that cause the outer segment to snap under pressure. The new experimental and theoretical findings help to explain the origin of severe eye diseases and could lead to new ways of preventing blindness.

"To our knowledge, this is the first theory that explains how the structural rigidity of the outer segment can make it prone to damage," says senior study author Aphrodite Ahmadi of the State University of New York Cortland. "Our theory represents a significant advance in our understanding of retinal degenerative diseases."

The outer segment of photoreceptors consists of discs packed with a light-sensitive protein called rhodopsin. Discs made at nighttime are different from those produced during the day, generating a banding pattern that was first observed in frogs but is common across species. Mutations that affect photoreceptors often destabilize the outer segment and may damage its discs, leading to cell death, retinal degeneration, and blindness in humans. But until now, it was unclear which structural properties of the outer segment determine its susceptibility to damage.

To address this question, Ahmadi and her team examined tadpole photoreceptors under the microscope while subjecting them to fluid forces. They found that high-density bands packed with a high concentration of rhodopsin were very rigid, which made them more susceptible to breakage than low-density bands consisting of less rhodopsin. Their model confirmed their experimental results and revealed factors that determine the critical force needed to break the outer segment.

The findings support the idea that mutations causing rhodopsin to aggregate can destabilize the outer segment, eventually causing blindness. “Further refinement of the model could lead to novel ways to stabilize the outer segment and could delay the onset of blindness,” says Ahmadi.

Specific protein essential for healthy eyes

Researchers at the Hebrew University of Jerusalem, in collaboration with researchers at the Salk Institute in California,  have found for the first time that a specific protein is essential not only for maintaining a healthy retina in the eye, but also may have implications for understanding and possibly treating other conditions in the immune, reproductive, vascular and nervous systems, as well as in various cancers.

Their work, reported online in the journal Neuron, highlights the role of Protein S in the maintenance of a healthy retina through its involvement in the process of pruning photoreceptors, the light-sensitive neurons in the eye. (This process is also referred to as phagocytosis.) These photoreceptors keep growing and elongating from their inner end. In order to maintain a constant length, they must be pruned from their outer end by specialized cells called retinal pigment epithelial cells.

Without such pruning — which also clears away many free radicals and toxic by-products generated during visual biochemical reactions — photoreceptors would succumb to toxicity and degenerate, leading if unchecked to blindness. A receptor molecule called Mer is a key in photoreceptor pruning, and is therefore vital for retinal health. Mutations in the mouse, rat and human Mer genes cause retinal degeneration, which finally leads to blindness.

The Hebrew University study published in Neuron focuses on the molecules activating Mer in this pruning mechanism. Although two such molecules – Gas6 and Protein S — were identified previously, it was yet to be proven that they also play a role in a living organism. To show this, Dr. Tal Burstyn-Cohen of the Hebrew University Institute of Dental Sciences and colleagues at the Salk Institute in California found in their experiments on laboratory animals that both Gas6 and Protein S are needed to activate phagocytosis, or pruning, of retinal photoreceptors, and thus keep a healthy retina.

These findings could have practical implications, since Protein S also functions as a potent blood anticoagulant. People with Protein S deficiency are at risk for life threatening thrombosis (blood clots) and thromboembolism (a clot that breaks loose and is carried by the blood stream to plug another vessel).

These results further open new avenues of research into the role of Protein S in activating the receptors in other tissues where their function was shown to be important, such as in the immune, reproductive, vascular and nervous systems, as well as in various cancers where activation of receptors has been observed. For example, since Protein S is important for blood vessel formation, neutralizing Protein S in the blood vessels supplying blood to cancer growths could interfere with the cancerous blood supply.

(Image: Gemma Bou/Getty Images)

Totally blind mice get sight back

Totally blind mice have had their sight restored by injections of light-sensing cells into the eye, UK researchers report. The team in Oxford said their studies closely resemble the treatments that would be needed in people with degenerative eye disease. Similar results have already been achieved with night-blind mice.

Experts said the field was advancing rapidly, but there were still questions about the quality of vision restored. Patients with retinitis pigmentosa gradually lose light-sensing cells from the retina and can become blind. The research team, at the University of Oxford, used mice with a complete lack of light-sensing photoreceptor cells in their retinas. The mice were unable to tell the difference between light and dark.

Reconstruction

They injected “precursor” cells which will develop into the building blocks of a retina once inside the eye. Two weeks after the injections a retina had formed, according to the findings presented in the Proceedings of the National Academy of Sciences journal. Prof Robert MacLaren said: “We have recreated the whole structure, basically it’s the first proof that you can take a completely blind mouse, put the cells in and reconstruct the entire light-sensitive layer.”

Previous studies have achieved similar results with mice that had a partially degenerated retina. Prof MacLaren said this was like “restoring a whole computer screen rather than repairing individual pixels”. The mice were tested to see if they fled being in a bright area, if their pupils constricted in response to light and had their brain scanned to see if visual information was being processed by the mind.

Vision

Prof Pete Coffee, from the Institute of Ophthalmology at University College London, said the findings were important as they looked at the “most clinically relevant and severe case” of blindness. “This is probably what you would need to do to restore sight in a patient that has lost their vision,” he said.

However, he said this and similar studies needed to show how good the recovered vision was as brain scans and tests of light sensitivity were not enough. He said: “Can they tell the difference between a nasty animal and something to eat?”

Prof Robin Ali published research in the journal Nature showing that transplanting cells could restore vision in night-blind mice and then showed the same technique worked in a range of mice with degenerated retinas. He said: “These papers demonstrate that it is possible to transplant photoreceptor cells into a range of mice even with a severe level of degeneration. “I think it’s great that another group is showing the utility of photoreceptor transplantation.”

Researchers are already trialling human embryonic stem cells, at Moorfields Eye Hospital, in patients with Stargardt’s disease. Early results suggest the technique is safe but reliable results will take several years.

Retinal chips or bionic eyes are also being trailed in patients with retinitis pigmentosa.