Posts Tagged ‘blindness’

Stem Cells Can Repair A Damaged Cornea

April 24th, 2012

A new cornea may be the only way to prevent a patient going blind – but there is a shortage of donated corneas and the queue for transplantation is long. Scientists at the Sahlgrenska Academy have for the first time successfully cultivated stem cells on human corneas, which may in the long term remove the need for donators.

Approximately 500 corneal transplantations are carried out each year in Sweden, and about 100,000 in the world. The damaged and cloudy cornea that is turning the patient blind is replaced with a healthy, transparent one. But the procedure requires a donated cornea, and there is a severe shortage of donated material. This is particularly the case throughout the world, where religious or political views often hinder the use of donated material.

Replacing donated corneas
Scientists at the Sahlgrenska Academy, University of Gothenburg, have taken the first step towards replacing donated corneas with corneas cultivated from stem cells.

Scientists Charles Hanson and Ulf Stenevi have used defective corneas obtained from the ophthalmology clinic at Sahlgrenska University Hospital in Mölndal. Their study is now published in the journal Acta Ophthalmologica, and shows how human stem cells can be caused to develop into what are known as “epithelial cells” after 16 days’ culture in the laboratory and a further 6 days’ culture on a cornea. It is the epithelial cells that maintain the transparency of the cornea.

Scientist Charles Hanson

First time ever on human corneas
“Similar experiments have been carried out on animals, but this is the first time that stem cells have been grown on damaged human corneas. It means that we have taken the first step towards being able to use stem cells to treat damaged corneas”, says Charles Hanson.

“If we can establish a routine method for this, the availability of material for patients who need a new cornea will be essentially unlimited. Both the surgical procedures and the aftercare will also become much more simple”, says Ulf Stenevi.

Few clinics conduct tranplants
Only a few clinics are currently able to transplant corneas. Many of the transplantations in Sweden are carried out at the ophthalmology clinic at Sahlgrenska University Hospital, Department of Ophthalmology, Mölndal.

The article “Transplantation of human embryonic stem cells onto a partially wounded human cornea in vitro” was published in Acta Ophthalmologica on 27 January.

www.sahlgrenska.gu.se

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University of Florida Researchers Develop Gene Therapy That Could Correct Blindness

March 6th, 2012

A new gene therapy method developed by University of Florida researchers has the potential to treat a common form of blindness that strikes both youngsters and adults. The technique works by replacing a malfunctioning gene in the eye with a normal working copy that supplies a protein necessary for light-sensitive cells in the eye to function. The findings are published in the Proceedings of the National Academy of Sciences online.

Several complex and costly steps remain before the gene therapy technique can be used in humans, but once at that stage, it has great potential to change lives.

“Imagine that you can’t see or can just barely see, and that could be changed to function at some levels so that you could read, navigate, maybe even drive — it would change your life considerably,” said study co-author William W. Hauswirth, Ph.D., the Rybaczki-Bullard professor of ophthalmology in the UF College of Medicine and a professor and eminent scholar in department of molecular genetics and microbiology and the UF Genetics Institute. “Providing the gene that’s missing is one of the ultimate ways of treating disease and restoring significant visual function.”

William W. Hauswirth, Ph.D. and Alfred S. Lewin, Ph.D.

The researchers tackled a condition called X-linked retinitis pigmentosa, a genetic defect that is passed from mothers to sons. Girls carry the trait, but do not have the kind of vision loss seen among boys. About 100,000 people in the U.S. have a form of retinitis pigmentosa, which is characterized by initial loss of peripheral vision and night vision, which eventually progresses to tunnel vision, then blindness. In some cases, loss of sight coincides with the appearance of dark-colored areas on the usually orange-colored retina.

The UF researchers previously had success pioneering the use of gene therapy in clinical trials to reverse a form of blindness known as Leber’s congenital amaurosis. About 5 percent of people who have retinitis pigmentosa have this form, which affects the eye’s inner lining.

“That was a great advance, which showed that gene therapy is safe and lasts for years in humans, but this new study has the potential for a bigger impact, because it is treating a form of the disease that affects many more people,” said John G. Flannery, Ph.D., a professor of neurobiology at the University of California, Berkeley who is an expert in the design of viruses for delivering replacement genes. Flannery was not involved in the current study.

The X-linked form of retinitis pigmentosa addressed in the new study is the most common, and is caused by degeneration of light-sensitive cells in the eyes known as photoreceptor cells. It starts early in life, so though affected children are often born seeing, they gradually lose their vision.

“These children often go blind in the second decade of life, which is a very crucial period,” said co-author Alfred S. Lewin, Ph.D., a professor in the UF College of Medicine department of molecular genetics and microbiology and a member of the UF Genetics Institute. “This is a compelling reason to try to develop a therapy, because this disease hinders people’s ability to fully experience their world.”

Both Lewin and Hauswirth are members of UF’s Powell Gene Therapy Center.

The UF researchers and colleagues at the University of Pennsylvania performed the technically challenging task of cloning a working copy of the affected gene into a virus that served as a delivery vehicle to transport it to the appropriate part of the eye. They also cloned a genetic “switch” that would turn on the gene once it was in place, so it could start producing a protein needed for the damaged eye cells to function.

After laboratory tests proved successful, the researchers expanded their NIH-funded studies and were able to cure animals in which X-linked retinitis pigmentosa occurs naturally. The injected genes made their way only to the spot where they were needed, and not to any other places in the body. The study gave a good approximation of how the gene therapy might work in humans.

“The results are encouraging and the rescue of the damaged photoreceptor cells is quite convincing,” said Flannery, who is on the scientific advisory board of the Foundation Fighting Blindness, which provided some funding for the study. “Since this type of study is often the step before applying a treatment to human patients, showing that it works is critical.”

The researchers plan to repeat their studies on a larger scale over a longer term, and make a version of the virus that proves to be safe in humans. Once that is achieved, a pharmaceutical grade of the virus would have to be produced and tested before moving into clinical trials in humans. The researchers will be able to use much of the technology they have already developed and used successfully to restore vision.

University of Florida

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Report Shows Risk of Blindness Halved Over Last Decade

February 21st, 2012

Age-related macular degeneration (AMD) is the most frequent cause of blindness in the Western World. A report from the University of Copenhagen and Glostrup Hospital in Denmark shows the number of new cases of blindness and severe visual loss in Denmark has been halved during the last ten years.

The study published in American Journal of Ophthalmology examined the records of 11,848 new cases of legal blindness. The rate of blindness from AMD fell from 522 cases per million inhabitants aged 50 years or older in 2000, to 257 cases per million in 2010, a reduction by over 50 per cent.

The bulk of the decrease occurred after 2006, following the introduction of new effective treatment for wet AMD, which is characterized by leaking blood vessels having formed under the fovea. The treatment consists of repeated injections into the eye of a medication that inhibits the signalling molecule vascular endothelial growth factor (VEGF).

Similar findings in Israel
The observations from Denmark were published together with a corroborating report from Israel that found comparable changes in the incidence of legal blindness in that country. Read the report “Time Trends in the Incidence and Causes of Blindness in Israel”.

Current treatment of wet AMD, also called neovascular AMD, consists of repeated injections into the vitreous, an inner compartment of the eye, of a medication designed to inhibit the action of VEGF. VEGF is a distress signal released from ailing cells of the aging retina. VEGF can cause formation of brittle blood vessels that leak blood and cause scar formation under the fovea. The fovea is central area of the retina where reading vision is located. Wet AMD is a very frequent cause of loss of reading vision.

Michael Larsen

Results show impact on public health
One of the authors behind the Danish study, Michael Larsen, Professor of Clinical Ophthalmology at the University of Copenhagen, is excited about the results.

“The massive implementation of modern wet AMD therapy has been a challenge. It is therefore very important that we can now show an impact on public health and it is wonderful to see a reduction in severe visual loss. The study did not examine moderate visual loss, but there are undoubtedly also a lot of people who avoided loosing their drivers license and their reading vision,” says Michael Larsen.

A turning point in eye care
The data for the study is provided by Danish Association of the Blind, which membership enrollment during the period of 2000-2010 was charted and categorized by diagnoses.

“The reduction in new cases of blindness is a turning point for eyecare in Denmark. We look forward to seeing further progress in eye research, especially in the hereditary eye diseases that cause blindness in children and young adults,” says Thorkild Olesen, Chairman of the Danish Association of the Blind.

www.ku.dk

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Chlamydia Trachomatis Bacteria Used as a Vaccine To Prevent Trachoma, The World’s Leading Cause of Infectious Blindness

November 25th, 2011

An attenuated, or weakened, strain of Chlamydia trachomatis bacteria can be used as a vaccine to prevent or reduce the severity of trachoma, the world’s leading cause of infectious blindness, suggest findings from a National Institutes of Health study in monkeys.

Anthony S. Fauci, M.D.

“This work is an important milestone in the development of a trachoma vaccine,” noted Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. “If this approach demonstrates continued success, the implications could be enormous for the tens of millions of people affected by trachoma, a neglected disease of poverty primarily seen in Asia and sub-Saharan Africa.”

In their study, published in the Journal of Experimental Medicine online, scientists from NIAID, led by Harlan Caldwell, Ph.D., describe how they tested their vaccine concept in a series of experiments. First they infected six cynomolgus macaques with the strain of C. trachomatis that they had weakened by removing a small piece of DNA. The scientists observed that the monkeys spontaneously cleared the infection within 14 days with no or minimal signs of ocular disease. The animals then were exposed twice more to the weakened strain at four- and eight-week intervals, but the animals still showed no signs of trachoma despite being infected.

Harlan Caldwell, Ph.D.

According to Dr. Caldwell, this finding is particularly significant because repeated C. trachomatis infections typically lead to more severe eye disease in people. The infected animals did not develop eye disease, and they all mounted robust immune responses.

The same six macaques then were exposed to a highly virulent strain of C. trachomatis as were six other macaques in a control group that had not been vaccinated. Three of the macaques in the vaccine group showed no signs of infection or disease, and the three others showed greatly reduced infection compared with monkeys in the control group. All six macaques in the control group became infected and displayed moderate to severe eye disease that persisted for between two and four months.

Macaques are used in trachoma studies because their immune responses closely predict those of humans. The animals in the study were treated with antibiotics after completion of the experiments, and all recovered completely.

The NIAID researchers are currently exploring how they can move their vaccine into human clinical trials.

Tracomatous Scarring: The presence of scarring in the tarsal conjunctiva. Scars are easily visible as white lines, bands, or sheets in the tarsal conjunctiva.

If left untreated, prolonged trachoma infection can cause a person’s eyelids to fold inward, so that the eyelashes rub the eyeball and scar the cornea. This can result in impaired vision and sometimes blindness. Trachoma is treatable with antibiotics, although in many parts of the world people have limited access to treatment. Currently, there is no vaccine for trachoma. Trachoma experts estimate that approximately 1.3 million people are blind from trachoma, 1.8 million people have low vision as a result of the disease, and an estimated 40 million people have active trachoma. Trachoma is most often spread through direct personal contact, shared towels and other cloths, and flies that have come in contact with the eyes or nose of an infected person.

Chlamydia diseases include sexually transmitted infections, which can result in pelvic inflammatory disease that can cause infertility in women, as well as trachoma. According to the NIAID researchers, findings from this study also could lead to the development of a vaccine against sexually transmitted Chlamydia infections. The Centers for Disease Control and Prevention received more than 1.2 million reports of Chlamydia infections in 2009.


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Canadians Not Doing Enough To Protect Themselves From The “Silent Thief of Sight”

November 15th, 2011

Dr. Cindy Hutnik

Glaucoma is the second leading cause of blindness worldwide. Although it can be treated, new research shows Canadians may not be doing enough to protect themselves. According to a new study by Lawson Health Research Institute’s Dr. Cindy Hutnik, many Canadian glaucoma patients are not screened until the disease has reached moderate or advanced stages.

Glaucoma is known as the “silent thief of sight.” It slowly and irreversibly destroys the optic nerve – so slowly, in fact, that many people don’t realize they have glaucoma until it reaches advanced stages. To maintain eye health, preventive screening is vital. Yet despite a spectrum of known risk factors, it appears many Canadians are not checking for them.

In a multi-centre study, Hutnik and her colleagues examined the risk factors shared by 404 newly diagnosed patients across 18 Canadian locations. Each was assessed for demographic information, medical history, and ocular family history, as well as a complete eye exam. Results were largely consistent with the international standards, confirming older age, structural abnormalities and deterioration, and high intraocular pressure as leading glaucoma risk factors. In a surprising twist, however, 48% of these new diagnoses – nearly half – were already at moderate to advanced stages.

It is not clear why Canadians are not screening for glaucoma earlier. Researchers suspect the slow disease progression may not project the same urgency as, for example, a broken limb. The additional cost of screening, which is not covered by OHIP, may also be a deterrent. Researchers have even suggested that available screening measures may not be sensitive enough to detect the complex spectrum of risk factors at early stages. While investigation continues, Dr. Hutnik urges Canadians to keep a close eye on the situation.

“Almost half to two-thirds of your optic nerve is dead before you even get a visual field defect,” she explains. “If you’re late getting your clinical screening test, the nerve has been dying for a long time and once it’s dead, it’s dead. You can only prevent it from getting worse.”

Dr. Hutnik is an Associate Scientist at Lawson’s Centre for Clinical Investigation and Therapeutics, and a Physician at the Ivey Eye Institute at St. Joseph’s Health Care London. She is also a Professor in the Departments of Ophthalmology and Pathology at The University of Western Ontario, and an Adjunct Professor in the Department of Chemistry & Biochemistry and the University of Windsor.

www.lawsonresearch.com

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Researchers Have Achieved Temporary Functional Preservation of Photoreceptors Using Gene Therapy

November 14th, 2011

Stephen Tsang, MD, Ph.D

In a paper published in the October 2011 issue of Experimental Biology and Medicine, a team of researchers at Columbia University Medical Center led by Stephen Tsang, MD, Ph.D have achieved temporary functional preservation of photoreceptors in a mouse model for retinitis pigmentosa (RP) using novel bipartite gene therapy.

RP is a heterogeneous disorder characterized by progressive degeneration of rod photoreceptors (which mediate night vision) causing night blindness and eventually total blindness. About 36,000 cases of simplex and familial RP worldwide are caused by mutant phosphodiesterase (PDE6). Says Dr. Tsang,

“Victor McKusick’s Mendelian Inheritance in Man catalog has approximately 4,000 genetic disease entries, but only 4 of these are already curable by gene-therapy approaches. This bipartite vector, which allows cell-specific delivery of both the normal gene and shRNA to knockdown other genes in the pathway, represents a strategy that may help cure many more retinal degenerations. Degeneration of rod photoreceptors also affects approximately 9 million Americans with age-related macular degeneration. Strategies to save photoreceptors in mouse models of RP may be applicable to that disease as well.”

In spite of this high prevalence, the interplay between defective PDE metabolism and RP pathogenesis remains poorly understood. In several mouse models for RP, defects in the PDE6B enzyme result in increased levels of the signaling molecules cGMP (mediated by GUCY2E cyclase) and Ca2+ (mediated by the CNGA1 channel).

Several aspects of the EBM report are innovative. It not only tackles the lack of functional PDE6â (by augmenting function with conventional gene replacement), but simultaneously counteracts the central biochemical impact of that lost function by decreasing abnormally accumulated cGMP and Ca2+. Furthermore, they used a tissue-specific promoter to achieve cell-specific expression of the transduced genes, which is unusual for shRNA delivery.

The researchers at Columbia developed three different lentiviral vectors, each of them designed to deliver wild-type Pde6b cDNA and one of two shRNAs. One vector delivered the cDNA and GUCY2E shRNA to reduce cGMP levels; another vector delivered the wild-type cDNA and CNGA1 shRNA to reduce Ca2+ levels; the third delivered the cDNA and the Gucy2e shRNA with a tissue-specific promoter. The bipartite approach was conceived as a way to improve therapeutic efficacy over that of a single-therapy approach, which was tested in an earlier project from Dr. Tsang’s lab. While the current project did not show improvement over their previous work, the researchers are optimistic that bipartite delivery may represent an important resource in future explorations of gene therapy in the eye and other tissues types.

A stem cell line was established and engineered to express green fluorescent protein (GFP) under control of the rod photoreceptor-specific Pde6g promoter through an internal ribosome entry site (IRES), Pde6g-IRES-GFP. The Pde6g-IRES-GFP cassette was introduced into mouse stem cells. The GFP marker is transcribed as a bicistronic message in conjunction with Pde6g. The GFP marker will only be expressed when these stem cells differentiate into rod photoreceptors (Fig. 2). Control retina is shown in the left (Fig. 1); whereas GFP marked photoreceptors are derived from stem cells found in Fig. 2. The Pde6g-IRES-GFP retinas show specific GFP marker expression in the outer nuclear layer marked by white arrows (Fig. 2).

Typical existing shRNA vector systems use the RNA polymerase III promoter, which is expressed in essentially all cell types, to drive expression of the transduced gene. However, expression of shRNA targeting GUCY2E in cone photoreceptors, which mediates color vision, would have unwanted and deleterious effects on vision. To achieve rod-specific expression of the shRNA, the researchers in this work embedded Gucy2e shRNA into the Pol II transcription unit of pre-miR34, which is expressed solely in rods. Similar methods can be used to target different tissues, so this method may have wide applicability.

The testing of shRNA therapeutic approaches in Pde6bH620Q mice should facilitate pre-clinical therapeutic evaluation of retinitis pigmentosa. Lessons learned from the proposed studies will eventually be translated into strategies for treatment trials in larger animal models of PDE6â deficiency, such as Irish Setter dogs, before seeing application in human therapeutics.

Dr. Steve Goodman, Editor-in-Chief of Experimental Biology and Medicine said, “Researchers at Columbia University Medical Center led by Stephen Tsang, MD, Ph.D have used a unique gene therapy approach to preserve photoreceptors and prolong functional vision in a mouse model of retinitis pigmentosa (RP). There work offers the promise of a future gene therapy cure for RP.”

www.cumc.columbia.edu

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Drug Shown To Improve Sight For Patients with Inherited Blindness

September 21st, 2011

Leber Hereditary Optic Neuropathy

A clinical trial led by Newcastle University shows that the drug, idebenone (Catena®), improved the vision and perception of colour in patients with Leber’s Hereditary Optic Neuropathy (LHON). The inherited condition means patients, who can see normally, lose the sight in one eye then within 3 to 6 months lose the sight in their other eye.

In some severely affected patients such as those who were unable to read any letters on the chart, the treatment with idebenone resulted in a marked improvement in their vision. In nine patients (12 eyes) out of 36 patients (61 eyes) taking idebenone, vision improved to the extent that patients were able to read at least one row of letters on the chart. In contrast not a single patient of the 26 who were taking the placebo improved to that extent.

Inherited from the mother, and mainly affecting men, LHON is caused by damage to the mitochondria in the eyes – the ‘batteries’ which power their cells. It is one of the most common causes of inherited blindness and is thought to affect around 2,000 people in the UK, around 10,000 in Europe and a further 10,000 in the USA.

“This is the first proven treatment for a mitochondrial disorder. We have seen patients who couldn’t even see an eye chart on the wall go on to read the first line down – and some even attempted the second line. For these patients, it can mean a vast improvement in their quality of life,” said Professor Patrick Chinnery, a Wellcome Trust Senior Fellow in Clinical Science at Newcastle University who also works at the Royal Victoria Infirmary in Newcastle – part of the Newcastle upon Tyne Hospitals NHS Foundation Trust.

Released today in the journal Brain published by Oxford University Press, the authors describe how patients with LHON were recruited from Newcastle Hospitals in the UK, in Munich, Germany and in Montreal, Canada for a double blind trial. Patients were either given idebenone for 24 weeks or a placebo.

At the end of the six months, some patients who were taking idebenone had improved vision and this is the first time a successful treatment has been found. The greatest improvement was seen in patients who had deteriorated in one eye more than the other.

Professor Chinnery explained: “We saw most progress in people who had better vision in one eye than the other – this tends to indicate that they are at an earlier stage of the condition. While we know that their vision is not what it once was, we also know that this treatment can dramatically improve their lives – some were able to move around more easily or even see family photos again.”

Idebenone penetrates into the mitochondria and is thought to mop-up toxic free radicals and enhance mitochondrial function. Previous research had provided anecdotal reports of improvements in vision but this is the first time it had been put to the test in a clinical trial. The drug company which sponsored this trial, Santhera Pharmaceuticals, is now seeking marketing approval from the European Medicines Agency for it to be offered as a standard form of treatment.

“We are hearing from patients that they still have improved vision – even though they are no longer taking the drug but we would like to verify this and study the effect further,” said Professor Chinnery. “There may also be a case for offering idebenone from the first moment that LHON is diagnosed – preferably before any symptoms are shown – and a further trial would ideally examine this.”

Mike Scholes, 58 from Lindfield in West Sussex, UK and a graduate of Newcastle University took part in the trial. He said: “I was training for a freefall parachute jump five years ago when I noticed I was having problems with my eye. I went for an eye test at the optician and on the way to pick up my glasses five days later, I nearly crashed the car. The optician tested my right eye and there was no problem, when he came to the left eye I asked him to switch on the machine – and he said he already had. I had lost the sight in my left eye in just five days.

“This meant an abrupt change in my life – I had a very successful hot air balloon business and I had to stop flying. I had to sell my cars as I could no longer drive.

“Following seven months of tests including CAT scans, X-Rays, MRI scans and a lumbar puncture, I was finally given a DNA test which revealed I had Leber’s hereditary optic neuropathy.

“It was around this time that my vision started to go in my second eye. I couldn’t see in an increasingly large area in the centre of my eyes and gradually colours disappeared. At worst the only colours I could make out were shades of blue.

“Soon after friends spotted a clinical trial in Newcastle, I volunteered to take part and started taking the tablets three times a day – not knowing whether I was taking a placebo or the drug.

“After just a month and a half I noticed that the area affected in the centre of my vision was smaller. The improvement continued and I began to appreciate colours again seeing yellow and most reds.

“Having Leber’s hasn’t stopped me enjoying life to the full – I run marathons with a guide, I’ve hiked to the North pole – but the noticeable improvement in my vision means daily life is easier. I can use a computerised viewer to help me read, I can get dressed without having to use a detector for the colours of clothes and while initially I couldn’t even see the eye chart, now if I get really close to a street sign I can read it.”


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Discovery May Shed Light on Common Causes of Blindness

September 9th, 2011

In a rare eye disease, the retina degenerates because light-receiving cells fail to regenerate, research led by a student at Case Western Reserve University School of Medicine shows.

The researchers include Dr. Samuel G. Jacobson’s group at the University of Pennsylvania and Dr. Andreas Engel’s group at University of Basel, Switzerland. They found that when the natural renewal process fails, metabolites are locked in, build up and turn toxic, killing cells over time in Enhanced S-Cone Syndrome.

A description of their work is online and will be published in print in the Journal of the Federation of American Societies for Experimental Biology today.

The discovery provides a target to treat and prevent blindness caused by the disease, also known as Goldmann-Favre Syndrome, which is found in about one in 1 million people.

But, more importantly the researchers say, the findings and the scientists’ use of two technologies to uncover the mechanisms leading to sight loss may help gain understanding of a broad array of retinal degenerative diseases, including macular degeneration, affecting millions worldwide.

“Although rare, Enhanced S-Cone Syndrome helps us understand critical visual processing errors that arise in disease,” said Debarshi Mustafi, who is earning his medical degree and PhD in pharmacology at Case Western Reserve. He is lead author of the study. “Knowing that photoreceptor cells affect their own renewal will surely have an impact on other, more common, forms of retinal degeneration.”

Dr. Samuel G. Jacobson

Enhanced S-Cone Syndrome is a condition in which the eye no longer has an orderly balance of cells called rods and cones, which enable us to see lights of different wavelengths, that is, different colors. Instead, cones that receive short wavelength light dominate and are clumped throughout the retina.

Those with the disease become night blind and progressively develop blind spots and lose sight as they age, until reaching blindness.

Dr. Andreas Engel

Genes connected to the disease have been known for some time. To find the molecular mechanism that causes sight loss, the researchers examined mouse models of the disease and 9 patients with the syndrome.

Optical imaging of the patients over a decade revealed an abnormal interface between the cones and the adjacent layer of tissue, called the retinal pigment epithelium.

Using gene-sequencing techniques on the mouse models, the team found expression of 30 genes involved in sight differed in healthy mice versus the disease models. Three of the genes were engaged in renewal of photoreceptors, a process called phagocytosis.

The researchers used a scanning electron microscope to produce images down to 100 nanometers, or the size of the largest holes in a surgical mask.

They found no phagosomes, essentially compartments made in cone cell membranes in which specialized cells called phagocytes of the retinal pigment epithelium eat cone material. In a healthy retina, phagosomes are present; phagocytes eat about 10 percent of the cone per day, continually renewing the cone.

The images instead showed bulbous cones in which metabolites that would normally be consumed remain, causing the swelling and turning toxic, the researchers said.

Analysis of cell cultures confirmed aberrations in the cones themselves were the cause of the problem, not the adjacent pigment layer as was previously thought.

“What we learn from this inherited human disease, and its mouse model, will be helpful to understand the aging process of the retina, like that seen in age-related macular degeneration,” said Krzysztof Palczweski, John H. Hord Professor and chair of the Department of Pharmacology at CWRU School of Medicine. Palzcweski is Mustafi’s advisor and senior author of the paper. “It is very likely that the phagocytotic process described in Debarshi’s paper is a dysfunction as we age.”

Mustafi said the methods that led to the discovery – combining gene sequencing and imaging – may have a wider impact. “It is a new way to study any disease.”

www.case.edu

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Stem Cell Therapy for Age-Related Macular Degeneration a Step Closer to Reality

April 1st, 2011

The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration has taken a significant step toward becoming a reality. In a study published in Stem Cells, Georgetown University Medical Center researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older Americans and worldwide. AMD gradually destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina.

While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient’s own stem cells to generate tissues and cells for transplantation.

For transplantation to be viable in age-related macular degeneration, researchers have to first figure out how to program the naïve hiPS cells to function and possess the characteristics of the native retinal pigment epithelium, RPE, the cells that die off and lead to AMD.

The research conducted by the Georgetown scientists shows that this critical step in regenerative medicine for AMD has greatly progressed.

“This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration,” says the study’s lead author Nady Golestaneh, Ph.D., assistant professor in GUMC’s Department of Biochemistry and Molecular & Cellular Biology.

Using an established laboratory stem cell line, Golestaneh and her colleagues show that RPE generated from hiPS cells under defined conditions exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression profile similar to those of a normal eye’s RPE.

“This isn’t ready for prime time though. We also identified some issues that need to be worked out before these cells are ready for transplantation but overall, this is a tremendous step forward in regenerative medicine,” Golestaneh adds.

She explains that the hiPS-derived RPE cells show rapid telomere shortening, DNA chromosomal damage and increased p21 expression that cause cell growth arrest. This might be due to the random integration of viruses in the genome of skin fibroblasts during the reprogramming of iPS cells. Therefore, generation of viral-free iPS cells and their differentiation into RPE will be a necessary step towards implementation of these cells in clinical application, Golestaneh says.

“The next step in this research is to focus on a generation of ‘safe’ as well as viable hiPS-derived somatic cells,” Golestaneh concludes.

Other authors on the paper include first author Maria Kokkinaki, Ph.D., Department of Biochemistry and Molecular &Cellular Biology, and Niaz Sahibzada, Ph.D., Department of Pharmacology at GUMC.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Georgetown Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO). In fiscal year 2009-2010, GUMC accounted for 79 percent of Georgetown University’s extramural research funding.

gumc.georgetown.edu

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