Scientists identify mutations that cause congenital cataracts

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Posted on 24th June 2011 by Pacific ClearVision Institute in Cataracts

New research identifies genetic mutations that cause an inherited form of cataracts in humans. The study, published online June 2 by Cell Press in the American Journal of Genetics, provides new insight into the understanding of lens transparency and the development of cataracts in humans.

A cataract is a clouding of the crystalline lens in the eye. Opacity of the normally transparent lens obstructs the passage of light into the eye and can lead to blindness. Congenital cataracts (CCs) are a significant cause of vision loss worldwide and underlie about one-third of the cases of blindness in infants. “Autosomal-recessive CCs form a clinically diverse and genetically heterogeneous group of lens disorders,” explains senior study author Dr. J. Fielding Hejtmancik from the National Eye Institute in Bethesda, Maryland. “Although several genes and genetic regions have been implicated in the rare nonsyndromic form of autosomal-recessive CCs, in many cases the mutated gene remains unknown or uncharacterized.”

One candidate gene that has been identified as playing a role in lens biology and in the pathogenesis of autosomal-recessive CCs is FYCO1. As part of an ongoing collaboration between the National Eye Institute in Bethesda MD and the National Center for Excellence in Molecular Biology and the Allama Iqbal Medical College in Lahore, Pakistan, Dr. Hejtmancik and colleagues performed a sophisticated genome-wide analysis of unrelated consanguineous families (in which both parents are descended from the same ancestor) of Pakistani origin and identified mutations in FYCO1 in 12 Pakistani families and one Arab Israeli family with autosomal-recessive CCs. The researchers went on to show that FYCO1 is expressed in the embryonic and adult mouse lens.

Both the high frequency of FYCO1 mutations and the recessive inheritance pattern seen in the families support the idea that autosomal-recessive CCs might result from a loss of FYCO1 function. The FYCO1 protein has been shown to play a role in “autophagy,” a process that is necessary for degrading unwanted proteins. To become transparent, lens cells must get rid of some of their protein components, and the researchers suggest that as lens cells lose their organelles during development, abnormal accumulation of protein aggregates might play a role in the loss of lens transparency.

Taken together, the results implicate FYCO1 in lens development and transparency in humans and FYCO1 mutations as a cause of autosomal-recessive CCs in the Pakistani population. “Our study provides a new cellular and molecular entry point to understanding lens transparency and human cataract,” concludes Dr. Hejtmancik. “In addition, because of the frequency of FYCO1 mutation in the Pakistani population, it might be useful in genetic diagnosis and possible even improved future cataract treatment and prevention.”

Sight Requires Exact Pattern of Neural Activity to Be Wired in the Womb

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Posted on 24th June 2011 by Pacific ClearVision Institute in Retina

The precise wiring of our visual system depends upon the pattern of spontaneous activity within the brain that occurs well before birth, a new study by Yale researchers shows.

“It isn’t just the genes. What happens within the womb is crucial,” said Michael Crair, the William Ziegler III Associate Professor of Vision Research at Yale School of Medicine and senior author of the study published in the June 23 issue of Neuron.

The extent of the roles of nature and nurture in the development of neural circuitry has long been debated. Scientists know genes provide the basic plan for brain development initially, and connections between brain cells are fine-tuned later in development.

But how does experience influence the wiring of the visual system in mammals, which have relatively long gestation periods during which the fetus is never visually stimulated? The answer apparently lies in the spontaneous pattern of neural activity generated by the brain itself.

Crair and his team genetically manipulated the retina of mice early in their development in ways that affected the pattern, but not the overall levels, of neural activity. They found that the visual system in these mice never developed properly.

“If experience plays a role in neural development, it is hard to explain how vision would be affected before birth because we do not see anything in the womb,” Crair said. “But we found that it is actually the pattern of ongoing spontaneous activity in the developing retina, not genes alone, that play a crucial in the development of the visual system.”

That means environmental disruption of these neural patterns during development could be damaging to the formation of these neural circuits. Crair notes that the team managed to alter these patterns by manipulating nicotinic acetylcholine receptors — the same receptors that are targeted by nicotine.

“It is possible that nicotine exposure would have a negative influence on neuronal connectivity of a child’s brain, even in the womb,” he said.

Lead author of the paper is Hong-ping Xu, of Yale. Other authors from Yale are Moran Furman, Yann S. Mineur, Hui Chen, Sarah L. King, David Zenisek, Z.Jimmy Zhou, Ning Tian and Marina R. Picciotto.

Primary funding for the research was provided by the National Institutes of Health.

Progress Using Induced Pluripotent Stem Cells to Reverse Blindness

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Posted on 24th June 2011 by Pacific ClearVision Institute in Retina

Researchers have used cutting-edge stem cell technology to correct a genetic defect present in a rare blinding disorder, another step on a promising path that may one day lead to therapies to reverse blindness caused by common retinal diseases such as macular degeneration and retinitis pigmentosa which affect millions of individuals.

In a study appearing in an advance online publication of the journal Stem Cells on June 15, 2011, investigators used recently developed technology to generate induced pluripotent stem (iPS) cells from a human patient with an uncommon inherited eye disease known as gyrate atrophy. This disorder affects retinal pigment epithelium (RPE) cells, the cells critical to the support of the retina’s photoreceptor cells, which function in the transmission of messages from the retina to parts of the brain that interpret images.

“When we generate iPS cells, correct the gene defect that is responsible for this disease, and guide these stem cells to become RPE cells, these RPE cells functioned normally. This is exciting because it demonstrates we can fix something that is out of order. It also supports our belief that in the future, one might be able to use this approach for replacement of cells lost or malfunctioning due to other more common diseases of the retina,” said lead study author cell biologist Jason Meyer, Ph.D., assistant professor of biology in the School of Science at Indiana University-Purdue University Indianapolis.

Macular degeneration is the most common cause of blindness, affecting an estimated 25-30 million people worldwide. One and a half million people worldwide are affected by retinitis pigmentosa.

Because iPS cells can be derived from the specific patient who needs them, use of these cells may avoid the problem of transplant rejection. In the study, vitamin B-6 also was used to treat the damaged RPE cells producing healthy cells that functioned normally. The retina is a relatively easily accessible part of the central nervous system, which makes it an attractive target for correction with iPS cells. Researchers are hopeful that once the gene defect responsible for a blinding disorder is corrected in iPS cells, these cells may be able to restore vision.

In addition to Meyer of the School of Science at IUPUI, “Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment” is co-authored by Sara E. Howden, Kyle A. Wallace, Amelia D. Verhoeven, Lynda S. Wright, Elizabeth E. Capowski, Jessica M. Martin, Shulan Tian, Ron Stewart, Bikash Pattnaik, James Thomson and David M. Gamm, all of the University of Wisconsin; and Isabel Pinilla of Blesa University Hospital and the Instituto Aragones de Ciencias de la Salud in Spain. Meyer is also a primary investigator with the Stark Neurosciences Research Institute at Indiana University School of Medicine. Thomson is also associated with the University of California — Santa Barbara.

Protein Unique to Avian Retina Contributes to Visual Acuity by Helping Eyes ‘Breathe’

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Posted on 24th June 2011 by Pacific ClearVision Institute in Retina

Say what you will about bird brains, but our feathered friends sure have us — and all the other animals on the planet — beat in the vision department, and that has a bit to do with how their brains develop.

Consider the in-flight feats of birds of prey: They must spot their dinner from long distances and dive-bomb those moving targets at lightning speed. And then there are the owls, which operate nimbly on even the darkest nights to secure supper in swift swoops. Some birds have ultraviolet sensitivity; others have infrared sensitivity. To boot, some birds can even see Earth’s magnetic field.

Much of the credit for avian visual acuity goes to the extraordinary retina, which grows out of the brain during development, making it an official component of the central nervous system. Indeed, the avian retina is far more complex in structure and composition than the human retina, and it contains many more photoreceptors — rod- and cone-shaped cells that detect light and color, respectively.

While researchers over the years have come to better understand much about the avian retina, many nagging questions remain. For Thorsten Burmester’s research team at the University of Hamburg, the question was this: How does such a productive retina sustain itself when the avian eye has very few capillaries to deliver oxygen to it? After all, it has to “breathe,” so to speak.

“The visual process in the vertebrate eye requires high amounts of metabolic energy and thus oxygen,” Burmester’s group writes in this week’s Journal of Biological Chemistry. “Oxygen supply of the avian retina is a challenging task because birds have large eyes, thick retinas and high metabolic rates, but neither deep retinal nor superficial capillaries.”

To answer the question, Burmester’s team took a closer look at a protein that they discovered exists in large quantities in photoreceptor cells of the avian eye — and only of the avian eye. They named the protein globin E. (The “E” is short for “eye,” of course.)

Burmester’s team used a number of techniques to characterize globin E and found that it is responsible for storing and delivering oxygen to the retina.

The finding is intriguing for a number of reasons.

Firstly, it helps explain how birds evolved to have such large eyes, relative to their body mass, without a dense network of ocular capillaries for blood delivery. (Some owls, for instance, have bigger eyes than humans.)

“The exact origin of globin E is still somewhat a mystery,” Burmester said. “It clearly evolved from some type of globin, but it has no obvious relative outside the birds.”

The globins are all thought to share a common ancestor, and the most well-known members of the family are myoglobin and hemoglobin. Myoglobin is responsible for oxygen storage and release in heart and skeletal muscle fibers. Hemoglobin, meanwhile, transports oxygen from the lungs to other parts of the body in red blood cells.

Burmester explains: “Bird eyes have evolved to have a system not unlike those in our heart, which uses myoglobin to store and release oxygen to maintain respiration and energy-consumption during muscle contraction. In eyes, oxygen and energy are needed to generate neuronal signals.”

Secondly, the finding puts to rest an earlier hypothesis that another molecule, neuroglobin, might be the oxygen-delivery vehicle for the avian eye. Neuroglobin is known to deliver oxygen to brain tissue, so it was only natural to suspect it. But it turns out that the messenger RNA fingerprint of globin E was 100-fold more prevalent than that of neuroglobin in Burmester’s chicken retina samples, indicating that neuroglobin probably has another, yet-to-be defined function in the avian eye.

Lastly, globin E is another interesting illustration of the convergent evolution of “myoglobin-like” molecules. Among the organisms with proteins with similar functions are the soybean, which needs its leghemoglobin to deliver oxygen to the Rhizobium soil bacteria that colonize in root nodules, and the 2-foot-long sea worm Cerebratulus lacteus, which needs its mini-hemoglobin to keep its brain and neurons oxygenated when it burrows deep into the sea floor, where oxygen levels are low, in search of clams.

After 55 Years, Surgery Restores Sight

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Posted on 24th June 2011 by Pacific ClearVision Institute in Retina

After being hit in the eye by a stone, a detached retina left a man blind in his right eye. Despite surgery to remove a cataract when the man was 23, which temporarily restored light perception, the patient was completely blind in that eye. Doctors at The New York Eye and Ear Infirmary have reported a case, published in BioMed Central’s open access Journal of Medical Case Reports, describing how this patient had functional vision restored 55 years after the childhood accident which left him blind.

Whilst it is unusual for a retina to become detached, common causes include head injury, myopia or diabetes. If a retina remains detached for a prolonged period of time, degenerative changes mean that it is often impossible to restore sight even if the retina is reattached. When the patient arrived at the hospital, complaining of pain, he was found to have total hyphema, neovascular glaucoma, high intraocular pressure and a detached retina. Doctors first treated the pressure to relieve his pain.

Once his eye pressure had stabilized they treated the neovascular glaucoma using monoclonal antibody therapy and found that against all odds the patient regained light perception. Encouraged by these results the doctors decided to try and reattach the retina. After surgery the man recovered his eyesight to such an extent that he could count fingers at a distance of five meters.

A year later the patient required further retinal surgery because scars inside his eye were forcing parts of the retina to become detached again. However this second surgery was also successful. Dr Olusola Olawoye said, “To the best of our knowledge this is the first report of visual recovery in a patient with long-standing traumatic retinal detachment. This is not only a great result for our patient but has implications for restoring eyesight in other patients, especially in the context of stem cell research into retinal progenitor cells which may be able to be transplanted into diseased retinas to restore vision.”

Retina Holds the Key to Better Vision in Deaf People

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Posted on 2nd June 2011 by Pacific ClearVision Institute in Retina

People who are deaf benefit from better vision due to the fact their retinas develop differently, experts at the University of Sheffield have shown.

The research, which was funded by RNID — Action on Hearing Loss and published June 1, 2011 in the journal PLoS ONE suggests that the retina of adults who are either born deaf or have an onset of deafness within the very first years of life actually develops differently to hearing adults in order for it to be able to capture more peripheral visual information.

Using retinal imaging data and correlating this with measures of peripheral vision sensitivity, a team led by Dr Charlotte Codina and Dr David Buckley from the University’s Academic Unit of Ophthalmology and Orthoptics, have shown that the retinal neurons in deaf people appear to be distributed differently around the retina to enable them to capture more peripheral visual information. This means that in deaf people, the retinal neurons prioritise the temporal peripheral visual field, which is what a person can see in their furthest peripheral vision, i.e. towards your ears.

Previous research has shown that deaf people are able to see further into the visual periphery than hearing adults, although it was thought the area responsible for this change was the visual cortex, which is the area of the brain that is particularly dedicated to processing visual information. This research shows for the first time that additional changes appear to be occurring much earlier on in visual processing than the visual cortex — even beginning at the retina.

The team also found an enlarged neuroretinal rim area in the optic nerve which shows that deaf people have more neurons transmitting visual information than hearing.

The findings were collected after the experts used a non-invasive technique called ocular coherence tomography (or OCT) to scan the retina. OCT works in a similar manner to ultrasound however uses light interference as opposed to sound interference.

Using this technique, it was possible to map the depth of retinal architecture including the depth of the neuron layer (retinal nerve fibre layer depth) and dimensions of the components of the optic nerve. All adults involved in the research were either severe/profoundly deaf or hearing and had their pupils dilated just before the retinal scans were taken. On a separate visit the participants had their visual fields measured in either eye to compare the retinal scan information with visual behaviour. The changes in retinal distribution were significantly correlated with the level of advantage individuals were showing in their peripheral vision.

Dr Charlotte Codina said: “The retina has been highly doubted previously as being able to change to this degree, so these results which show an adaptation to the retina in the deaf really challenge previous thinking.

“This is the first time the retina has been considered as a possibility for the visual advantage in deaf people, so the findings have implications for the way in which we understand the retina to work. Our hope is that as we understand the retina and vision of deaf people better, we can improve visual care for deaf people, the sense which is so profoundly important to them.”

Dr Ralph Holme, Head of Biomedical Research at RNID — Action on Hearing loss, says: “The better peripheral vision experienced by people who are deaf, in comparison to those who hear, has significant benefits for their everyday lives — including the ability to quickly spot hazards at the boundaries of their view. This research substantially improves our understanding of how changes in the retina create this advantage, and could help researchers identify ways to further enhance this essential sense for people who are born deaf.”

How Retinas Develop: Scientists Make Strides in Vision Research

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Posted on 2nd June 2011 by Pacific ClearVision Institute in Retina

New research at UC Santa Barbara is contributing to the basic biological understanding of how retinas develop. The study is part of the campus’s expanding vision research.

The new studies are published in recent online versions of The Proceedings of the National Academy of Sciences (PNAS), and Investigative Ophthalmology and Visual Science (IOVS).

The scientists document how they used mice as a research model organism to show that the size of different populations of retinal neurons display wide-ranging variability among individuals. In the PNAS article, they demonstrate a nearly two-fold variation in the number of interneurons called horizontal cells. In the IOVS article, they report a conspicuous variation in the number of cone photoreceptors.

“These studies individually demonstrate the genetic determinants of nerve cell number,” said Benjamin E. Reese, senior author and professor with the Neuroscience Research Institute and the Department of Psychological and Brain Sciences. “Together, they show that different nerve cell types are modulated independent of one another.”

Using recombinant inbred mice, Irene Whitney, graduate student and first author of both articles, and Mary Raven, staff scientist and co-author, have been able to identify genomic loci where polymorphic genes must contribute to such natural variation. In the IOVS article, they describe this natural variation for the population of cone photoreceptors, and identify two potential causal genes that may modulate cone photoreceptor production on chromosome 10.

In the PNAS article, the scientists — working will colleagues from four other U.S. institutions — identify a promising candidate gene at a locus on chromosome 13, a transcription factor gene called Islet-1. This gene was confirmed to be critical for regulating horizontal cell number in genetically modified mice, in which the Islet-1 gene was rendered nonfunctional. The scientists verified that expression of this gene differs between these strains of mice during the developmental period when horizontal cells are produced. They also showed that the source of this variable expression must be due to a genetic variant within a regulatory region of the gene itself. Finally, they identified such a single nucleotide polymorphism creating an E-box, a DNA sequence bound by a family of transcription factors that have recently been shown to play a role in retinal development.

The team explained that such natural variation in the ratio of nerve cells requires a degree of plasticity in the process of forming neural connectivity, to ensure that the entire visual field is served by neural circuits that mediate our visual abilities. A series of other published and submitted studies from the Reese lab document this very plasticity in different strains of mice and in genetically modified mice.

Efforts to use genetic engineering and stem cell biology to repair diseased retinas depend upon a fuller appreciation of the developmental biology of the retina, explained Reese.

“These particular studies are just one contribution in an enormously complex process,” said Reese. “Our fundamental interest is in the development the retina — how you ‘build’ this neural tissue that, when fully mature, will mediate our visual abilities.”

Vision research at UCSB has been steadily expanding in recent decades. “Since I arrived here in 1971, UCSB’s vision research has grown to include dozens of scientists, in a number of labs, contributing to an explosion of research in the field,” said Steven Fisher, professor emeritus in the Department of Molecular, Cellular, and Developmental Biology, and professor in the Neuroscience Research Institute.

The National Eye Institute of the National Institutes of Health funded both of the above studies.

Scientists Reveal Nerve Cells’ Navigation System

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Posted on 2nd June 2011 by Pacific ClearVision Institute in Retina

Johns Hopkins scientists have discovered how two closely related proteins guide projections from nerve cells with exquisite accuracy, alternately attracting and repelling these axons as they navigate the most miniscule and frenetic niches of the nervous system to make remarkably precise connections.

The discovery, reported April 28 in the journal Neuron, reveals that proteins belonging to the “semaphorin” family of guidance cues are crucial for getting neuronal projections exactly where they need to be not only across long distances, but also in the short-range wiring of tiny areas fraught with complex circuitry, such as the central nervous system of the fruit fly.

Because signaling that affects the growth and steering of neuronal processes is critical for repairing and regenerating damaged or diseased nerve cells, this research suggests that a more refined understanding of how semaphorin proteins work could contribute to treatment strategies, according to Alex Kolodkin, Ph.D., a professor in the neuroscience department at Johns Hopkins and a Howard Hughes Medical Institute investigator.

Using embryonic flies, some native (normal) and others genetically altered to lack a member of the semaphorin gene family or the receptor that binds to the semaphorin and signals within the responding neuron, the team labeled particular classes of neurons and then observed them at high resolution using various microscopy strategies to compare their axon projections.

In the native developing flies, the team saw how certain related semaphorins, proteins that nerve cells secrete into the intracellular space, work through binding their plexin receptor. First, a semaphorin-plexin pair attracts a certain class of extending neurons in the embryonic fly central nervous system assemble a specific set of target projections. Then, a related semaphorin that binds to that same plexin receptor repels these same neurons so as to position them correctly with in the central nervous system. Finally, the attractive semaphorin/plexin interaction assures the establishment of precise connections between these central nervous system axons and sensory neurons that convey messages about the external environment by extending their axons into the CNS from the periphery and contacting the assembled CNS pathways. Flies lacking this semaphorin/plexin signaling showed defects in these connections, which the researchers were able to reverse when these cues and receptors were re-introduced into flies lacking them.

To investigate whether the absence of semaphorin in flies had behavioral consequences, the team collaborated with investigators at Janelia Farm laboratories of the Howard Hughes Medical Institute and used specialized computer software to follow the movements of hundreds of fly larvae crawling on a small dish. The plate was perched on a large speaker that vibrated with pulses of sound, letting the team compare the movements of normal larvae to mutants missing semaphorin.

The “tracking” software measures differences in normal foraging behavior (mostly crawling straight and occasionally making turns) when a sound is activated. The larvae with intact semaphorin/plexin responded to sound stimulation by stopping, contracting and turning their heads from side to side. The semaphorin mutants failed to respond to the same stimuli. The researchers repeated the experiment using mutant larvae missing the protein to which semaphorin binds — its plexin receptor-and these larvae also showed no reaction to sound-vibration.

“The fly larvae sensory neurons, located on the larval body wall, send axon projections that do not make contact with their appropriate targets in the central nervous system when semaphorin/plexin signaling is absent,” Kolodkin says. “This tells us that semaphorin cues guide not only neuronal processes assembly in the central nervous system, but also incoming projections from sensory neurons to the CNS targets.”

The Kolodkin lab’s experiments in the invertebrate fruit fly central nervous system mirror related findings in the mouse reported Feb. 10, 2011 in Nature. Then, they showed that a different semaphorin cue is important for certain neurons to make precise connections within the developing inner plexiform layer of the retina, an elaborately laminated club-sandwich-like structure that must be precisely wired for accurate visual perception in mammals.

To demonstrate that semaphorins are necessary for neuronal projections from distinct classes of neurons to make their way to correct layers in this retinal “sandwich,” the scientists examined the retinas of 3-, 7- and 10-day-old mice that were genetically modified to lack either a member of the semaphorin gene family or its appropriate plexin receptor. These mutants showed severe connectivity defects in one specific inner plexiform layer, revealing faulty neuronal targeting.

“In two distinct neural systems in flies and mammals, the same family of molecular guidance cues — semaphorins and their receptors — mediate targeting events that require exquisite short-range precision to generate complex neuronal connectivity,” says Kolodkin who, as a postdoctoral fellow in the mid-1990s, first discovered the large family of semaphorin guidance cues working with the grasshopper nervous system.

“This work begins to tell us how, in a very small but highly ordered region of the nervous system, select target innervation and specific synaptic contacts between different classes of neurons can be established in the context of evolving circuit complexity” Kolodkin says.

The fly research appearing in Neuron was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

The mouse retina research appearing in Nature was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

Authors of the fly nervous system study published in Neuron, in addition to Kolodkin, are, Zhuhao Wu, Joseph C. Ayoob, Kayam Chak, and Benjamin J. Andreone, all of Johns Hopkins; Lora B. Sweeney and Liqun Luo, both of Stanford University; and Rex Kerr and Marta Zlatic, both of Janelia Farm Research Campus.

Authors of the mammalian retina study published in Nature, in addition to Kolodkin, are Ryota L. Matsuoka and Tudor C. Badea, both of Johns Hopkins; and KimT.Nguyen-Ba-Charvet, Aijaz Parray, and Alain Che┬┤dotal, all of the Institut de la Vision, Paris.

Sections of Retinas Regenerated and Visual Function Increased With Stem Cells from Skin

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Posted on 2nd June 2011 by Pacific ClearVision Institute in Retina

Scientists from Schepens Eye Research Institute are the first to regenerate large areas of damaged retinas and improve visual function using IPS cells (induced pluripotent stem cells) derived from skin. The results of their study, which is published in PLoS ONE this month, hold great promise for future treatments and cures for diseases such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and other retinal diseases that affect millions worldwide.

“We are very excited about these results,” says Dr. Budd A. Tucker, the study’s first author. “While other researchers have been successful in converting skin cells into induced pluripotent stem cells (iPSCs) and subsequently into retinal neurons, we believe that this is the first time that this degree of retinal reconstruction and restoration of visual function has been detected,” he adds. Tucker, who is currently an Assistant Professor of Ophthalmology at the University of Iowa, Carver College of Medicine, completed the study at Schepens Eye Research Institute in collaboration with Dr. Michael J. Young, the principle investigator of the study, who heads the Institute’s regenerative medicine center.

Today, diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are the leading causes of incurable blindness in the western world. In these diseases, retinal cells, also known as photoreceptors, begin to die and with them the eye’s ability to capture light and transmit this information to the brain. Once destroyed, retinal cells, like other cells of the central nervous system have limited capacity for endogenous regeneration.

“Stem cell regeneration of this precious tissue is our best hope for treating and someday curing these disorders,” says Young, who has been at the forefront of vision stem cell research for more than a decade.

While Tucker, Young and other scientists were beginning to tap the potential of embryonic and adult stem cells early in the decade, the discovery that skin cells could be transformed into “pluripotent” cells, nearly identical to embryonic cells, stirred excitement in the vision research community. Since 2006 when researchers in Japan first used a set of four “transcription factors” to signal skin cells to become iPSCs, vision scientists have been exploring ways to use this new technology. Like embryonic stem cells, iPSCs have ┬Čthe ability to become any other cell in the body, but are not fraught with the ethical, emotional and political issues associated with the use of tissue from human embryos.

Tucker and Young harvested skin cells from the tails of red fluorescent mice. They used red mice, because the red tissue would be easy to track when transplanted in the eyes of non-fluorescent diseased mice.

By forcing these cells to express the four Yamanaka transcription factors (named for their discoverer) the group generated red fluorescent IPSCs, and, with additional chemical coaxing, precursors of retinal cells. Precursor cells are immature photoreceptors that only mature in their natural habitat — the eye.

Within 33 days the cells were ready to be transplanted and were introduced into the eyes of a mouse model of retina degenerative disease. Due to a genetic mutation, the retinas of these recipient mice quickly degenerate, the photoreceptor cells die and at the time of transplant electrical activity, as detected by ERG (electroretinography), is absent.

Within four to six weeks, the researchers observed that the transplanted “red” cells had taken up residence in the appropriate retinal area (photoreceptor layer) of the eye and had begun to integrate and assemble into healthily looking retinal tissue.

The team then retested the mice with ERG and found a significant increase in electrical activity in the newly reconstructed retinal tissue. In fact, the amount of electrical activity was approximately half of what would be expected in a normal retina. They also conducted a dark adaption test to see if connections were being made between the new photoreceptor cells and the rest of the retina. In brief, the group found that by stimulating the newly integrated photoreceptor cells with light they could detect a signal in the downstream neurons, which was absent in the other untreated eye.

Based on the results of their study, Tucker and Young believe that harvesting skin cells for use in retinal regeneration is and will continue to be a promising resource for the future.

The two scientists say their next step will be to take this technology into large animal models of retinal degenerative disease and eventually toward human clinical trials.

Other scientists involved in the PLoS ONE study include In-Hyun Park, Sara D. Qi, Henry J. Klassen, Caihui Jiang, Jing Yao, Stephen Redenti, and George Q. Daley.

Scientists Hoping to Cure Blindness in Premature Babies

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Posted on 2nd June 2011 by Pacific ClearVision Institute in Retina

Scientists from the School of Medicine, Dentistry and Biomedical Sciences at Queen’s University Belfast are teaming up to develop a cure to an illness that can lead to blindness in premature babies, thanks to funding from children’s charity Action Medical Research.

Two teams from the Centre for Vision and Vascular Science at Queen’s are taking different approaches to a condition called Retinopathy of Prematurity (ROP). The condition can lead to blindness in premature babies, putting the youngest, sickest and smallest babies most at risk, including over 3,000 babies who are born more than 12 weeks early each year in the UK.

ROP is caused by blood vessels in the eye growing abnormally and causing damage to the retina — the light-sensitive inner lining of the eye. Evidence suggests it develops in two stages:

Stage 1. Premature babies have poorly developed lungs and need extra oxygen to help them breathe. Unfortunately the blood vessels that supply the eye’s light-sensitive retina are damaged by this additional oxygen and stop growing properly, meaning the retina does not get enough nutrients.

Stage 2. Eventually, in response to this damage, new vessels grow, in an attempt to rescue the retina, but they are abnormal and actually damage the eye, causing vision loss.

The first team, led by Dr Denise McDonald, has the aim of tackling the disease at a very early stage, which will minimise the damaging effects of ROP.

The second team, led by Dr Derek Brazil, is investigating whether stem cells from babies’ own umbilical cords might have the power to repair their damaged eyes and save their sight.

About one in ten babies with ROP develops severe disease, which threatens his or her sight. If this is detected early enough, laser treatment can save the most important part of a baby’s vision — the sharp, central vision we need to look straight ahead. However, this causes permanent loss of a baby’s peripheral vision and may induce short-sightedness. What’s more, it doesn’t always work, meaning some babies still go blind.

Dr Brazil believes it may be possible to protect babies from ROP, and save their sight, by treating them with a special type of stem cell taken from their own umbilical cords. Dr Brazil and his colleagues Dr Michelle Hookham, Dr Reinhold Medina and the Centre Director Professor Alan Stitt, were awarded a two-year grant by Action Medical Research, to undertake this important work.

He said: “We hope our laboratory work will reveal whether vascular stem cells have the potential to repair damage to babies’ eyes and save their sight. If so, it is possible that in the future vascular stem cells could be taken from a baby’s own umbilical cord just after birth and then grown in the laboratory in case treatment is needed.

Taking a different approach, Dr McDonald and her team are exploring a key step in the early stages of the disease process. While laser treatment tackles stage 2 of the disease process, by stopping abnormal blood vessels from growing, by this stage the disease can already be quite severe.

Dr McDonald and her team are looking for possible new treatments which will protect the retinal blood vessels from the effect of high oxygen which occurs in stage one.

Evidence suggests that certain cofactors protect and encourage normal growth of the delicate blood vessels that supply the retina, as long as they are present in sufficient quantities. In contrast, low levels of these cofactors seem to be linked to the destruction of blood vessels. The researchers are investigating the role of specific cofactors and ways to enhance their function as a possible treatment for ROP.

Dr Denise McDonald and her colleague, Dr Tom Gardiner, were awarded a two-year research grant from Action Medical Research for the project.

Dr Alexandra Dedman, Senior Research Evaluation Manager from Action Medical Research, said: “We are delighted to be funding these two expert research teams in Belfast who both have longstanding track records, recognised internationally. Their work in this area has the potential to change the lives of babies around the world suffering from this condition.”

Both Dr Brazil’s and Dr McDonald’s teams are based at the Centre for Vision and Vascular Science at Queen’s University Belfast, which contains state-of-the art facilities and equipment. The centre has a long history of successful research into many of the leading causes of vision loss. Both projects involve collaboration with Dr Eibhlin McLoone, consultant paediatric ophthalmologist at the Royal Victoria Hospital.