Microglia - a potential therapeutic target in Retinitis Pigmentosa

Spider-like cells inside the brain, spinal cord and eye hunt for invaders, capturing and then devouring them. These cells, called microglia, often play a beneficial role by helping to clear trash and protect the central nervous system against infection. But a new study by researchers at the National Eye Institute (NEI) shows that they also accelerate damage wrought by blinding eye disorders, such as retinitis pigmentosa.

New therapy holds promise for restoring vision in Retinitis Pigmentosa and Leber Congenital Amaurosis

Scientists from the University of California, Berkeley and Lawrence Berkeley National Laboratory, along with those of University of Pennsylvania, have demonstrated restoration of visual function in animal models that can help restore sight in blind patients afflicted by diseases such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA).

Human stem cell-derived retinal cells show promise as treatment for macular diseases

Note: The post below is  from the study (pdf) published in The Lancet.

Since 1981, when pluripotential cell cultures were first derived by Evans and Kauffman, embryonic stem cells (ESC) have been regarded as a potential source of therapeutic cells for a wide range of diseases caused by tissue loss or dysfunction. Despite the great therapeutic potential, their plasticity and unlimited capacity for self-renewal raise concerns about serious safety issues, including the ability to form teratomas and other tumours, potential immune reactions, and the risk of differentiating into unwanted cell types. 

Stem cells close to cornea may help treat Macular Degeneration or Retinitis Pigmentosa

Scientists at the Southampton General Hospital and the University of Southampton have found a pool of stem cells around the corneal limbus that can be induced to become retinal cells. Such cells can then potentially be transplanted into the eye of the patient of macular degeneration or retinitis pigmentosa to stop the disease or even cure it.  

Gene therapy for childhood blindness

Genzyme has announced the establishment of a research collaboration with the University of Florida (UF) and the University of Pennsylvania to develop gene therapy for the treatment for Leber congenital amaurosis type 1 (LCA-1), which is usually diagnosed in children who are less than a year old, and patients remain severely visually impaired for the rest of their lives. This disease, which is the most common cause of childhood blindness, is a group of degenerative diseases of the retina caused by genetic mutations in one of 19 genes currently associated with the disorder. These genes encode proteins that play a variety of roles in the development and function of the retina, and a mutation in any one of them can cause visual impairment.

Japanese woman is first recipient of next-generation iPS stem cells for macular degeneration

A Japanese woman in her 70s has become the first person in the world to receive retinal cells derived from induced pluripotent stem cells (iPS). In a two-hour procedure on September 12, 2014, a team of three eye specialists lead by Dr Yasuo Kurimoto of the Kobe City Medical Center General Hospital, Japan, implanted a 1.3 by 3.0 millimetre sheet made of retinal pigment epithelium (RPE) cells into one eye of this patient, who was diagnosed with age-related macular degeneration (AMD).

New technique to determine gene carriers for autosomal recessive retinitis pigmentosa

Scientists from Bascom Palmer Eye Institute and Duke University Medical Center have developed a non-invasive technique to determine if individuals carry a gene for the autosomal recessive type of retinitis pigmentosa. 

The work was being presented at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Orlando, Florida.

The technique involves collecting a patient's urine and measuring the ratio between specific compounds. The non-invasive process makes subsequent testing clinic-friendly, especially for children being screened.

In search of quantitative biomarkers for the disease, the authors checked on the urinary and plasma dolichol profiles in autosomal recessive RP (arRP) patients and carriers with mutations in the DHDDS gene encoding dehydrodolichol diphosphate synthase, a key enzyme in dolichol biosynthesis. Dolichols are long chain polyisoprenoid alcohols composed of 17-21 isoprene units.

Mutations in the DHDDS gene lead to a characteristic shortening of plasma and urinary dolichols, which, as per the authors of this study, can be used as a functional readout of the enzyme. Urinary and plasma D18/D19 ratios reliably determine if a DHDDS genotype is disease-causing. 

D18/D19 ratio is a viable objective functional biomarker and can be readily adapted as a clinical test for arRP diagnosis and carrier screening with DHDDS or other genetic mutations that impair dolichol biosynthesis.

Source

DENAQ, a new chemical that may restore sight in retinitis pigmentosa and macular degeneration

Scientists from the University of California, Berkeley report on a chemical ‘photoswitch’ named DENAQ that may be a potential drug for treating patients suffering from blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

RP and AMD are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. In the paper published in Neuron, the authors led by Dr Richard H Kramer report about a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight, compared to earlier attempts at photoswitch that required very bright ultraviolet light, making it unsuitable for use in patients. In experiments conducted on three-month to six-month-old healthy mice, and on mice carrying a mutation causing nearly all their rods and cones to degenerate by the time they were a month old, a single intraocular injection of DENAQ has been able to photosensitize the blind retina for about 3 days, restoring electrophysiological and behavioral responses with no toxicity. DENAQ also is able to rapidly turns itself off, allowing rapid repeated stimulation of the retina. The researchers compared the retinae of DENAQ-injected mice to untreated healthy mice and found no signs of toxicity for up to 30 days after the injection.

Retinas with damaged rods and cones are subject to several morphological and biochemical changes, making them different from a healthy retina in more than one way. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated or dead photoreceptors. Apparently, the degenerated outer retinal cells help in DENAQ photosensitization due to changes in electrophysiological characteristics, while the presence of intact photoreceptors possibly prevent this action. This appears to give it significant advantage, since this selective action on diseased tissue alone may potentially reduce side effects on healthy retina.

DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.

The researchers plan on conducting more experiments, including in larger animals before its safety can be established and any clinical trials can be considered.

To watch a video of Dr Kramer explaining his work, click here.

Sources: Neuron, Univ of California, Berkeley, Kramer Lab, The Scientist

Editor's note: The drug appears to have an exciting potential to help patients with retinitis pigmentosa and age-related macular degeneration. There are two thoughts though. 

1. Such a drug may only work in advanced stages of the disease, considering we will have to wait for the retinal cells to die before it can act.

2. We also need to know how long the effect of one injection lasts. Such treatment may require repeat injections over a long-term, something similar to Lucentis or Avastin.

Advanced Cell Technology initiates higher-dosage patient treatment in European clinical trial for Stargardt's Disease

Advanced Cell Technology, Inc., a pioneer in the field of stem cells for treating conditions such as macular degeneration. has announced treatment of the first patient in the third dosage cohort, and seventh patient overall, in its European Phase I clinical trial for Stargardt’s macular dystrophy (SMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs). 

The patient was injected with 150,000 hESC-derived RPE cells, as compared with the 100,000-cell dose used in patients of the second cohort. The surgery was performed on Friday, April 19, without any complications, and the patient is recovering uneventfully.

The company declared that they are past the halfway point in all three of their clinical trials on both continents. They have also announced that the European Medicines Agency's (EMA) Committee for Orphan Medicinal Products (COMP) has officially granted their hESC-derived RPE cells orphan medicinal product designation for the treatment of SMD. This will likely provide a number of benefits to them, as in protection from competition, as well as for the patients through reduced fees.

The Phase 1/2 trial is designed to determine the safety and tolerability of hESC-derived RPE cells following sub-retinal transplantation in patients with SMD at 12 months, the study’s primary endpoint. It will involve a total of 12 patients, with cohorts of three patients each in an ascending dosage format.

Stargardt’s disease or Stargardt’s Macular Dystrophy is a genetic disease that causes progressive vision loss, usually starting in children between 10 to 20 years of age. Eventually, blindness results from photoreceptor loss associated with degeneration in the pigmented layer of the retina, called the retinal pigment epithelium, which is the site of damage that the company believes the hESC-derived RPE may be able to target for repair after administration. Clink here to read more, 

Deluxe Healthcare and Grooming Set - Health Care (Google Affiliate Ad)

A study for new treatments for wet age-related macular degeneration (AMD)

A University of Wisconsin School of Medicine and Public Health scientist, Dr Nader Sheibani, is spearheading a study of new treatments for wet age-related macular degeneration (AMD). Dr. Sheibani, a professor in the department of ophthalmology and visual sciences, was awarded $6.2 million over five years from the National Eye Institute. In the first year, the collaborators will receive $1.2 million.

The project is a collaboration among Dr. Sheibani’s lab and others in the department of ophthalmology and visual sciences; researchers in the UW department of pediatrics; scientists at Northwestern University Center for Developmental Therapeutics and Feinberg School of Medicine; and the University of Nebraska Center for Drug Delivery and Nanomedicine. Each specialist and team brings different skills and techniques to the question of treatment of exudative AMD.

Wet or exudative AMD is the leading cause of blindness among aging Americans. The global rate of AMD is expected to double in the next decade as the population ages.  A cause of vision loss in this type of AMD is associated with angiogenesis, the growth of new blood vessels which are leaky with severe consequences to vision.

Ophthalmologists have developed treatments known as anti-vascular endothelial growth factor (VEGF) to slow or stop new vessels from forming. The anti-VEGF treatments require frequent injections into the eye. They are an important tool for ophthalmologists to help save vision and their use has demonstrated that inhibiting VEGF slows damage from AMD. However, VEGF is essential for normal ocular integrity and function. Therefore, there is a great need for new treatments which preserve vision without interfering with normal functions.

Dr. Sheibani and his collaborators hope to develop treatments using small peptides that mimic those of the body’s own inhibitors of angiogenesis. These treatments will counter VEGF activity and inhibit vascular growth in eyes with exudative AMD while providing an environment resistant to new vessel growth. 

This study will develop peptide mimetics – shorter versions of the proteins the body makes – that will stop vessel growth. Researchers at Northwestern University are developing the peptides and those at the University of Nebraska are developing the drug delivery nanotechnology. Dr. Sheibani and his staff will test whether the treatments work in preclinical models of the disease for its translation to humans.

The hope is that this class of drugs, because they mimic the body’s own defenses, will be more effective and have fewer side effects than the treatments already available. Although human clinical trials are years away, this research is truly translational, with the potential to greatly impact quality of life by preventing a common cause of vision loss.

Source

A new potential treatment for Retinitis Pigmentosa & Macular Degeneration

A team of researchers from the University of California, Berkeley, in collaboration with researchers at University of Munich and University of Washington in Seattle have found a chemical that can temporarily restore some amount of vision in blind mice.

This compound could eventually help those with Retinitis Pigmentosa, a common genetic disease that leads to blindness, as well as Age-related Macular Degeneration.

The chemical, referred to as AAQ, acts on the remaining cells in the retina, which are normally "blind" cells, sensitive to light. AAQ is a photoswitch that binds to protein ion channels on the surface of retinal cells; when switched on by light, it alters the flow of ions through the channels and activates these neurons similar to the way rods and cones are activated by light.

This chemical has been shown to eventually wear off, and hence may offer a safer alternative to other approaches that restore sight, such as gene or stem cell therapies, which may permanently change the retina. It is also less invasive than implanting light-sensitive chips in the eye.

Considering that it is a simple chemical, it will be easy to change the dosage, use it in combination with other therapies, or discontinue the therapy if the need be. This would allow new and improved chemicals that may become available in time to be offered to the same patients.

The blind mice in the experiment had genetic mutations that made their rods and cones die within months of birth and inactivated other photopigments in the eye. After injecting very small amounts of AAQ into the eyes of the blind mice, the researchers confirmed that they had restored light sensitivity because the mice's pupils contracted in bright light. The mice also demonstrated light avoidance, a typical rodent behavior impossible without the animals being able to see some light. The researchers are hoping to conduct more sophisticated vision tests in rodents injected with the next generation of the compound.

It will be a while before this compound will find its way in humans. The researchers have to show that these compounds are safe and will work in patients the way they work in mice. BUt these preliminary results demonstrate that this class of compound restores light sensitivity to retinas blind from genetic disease.

The current technologies being evaluated for restoring sight to people whose rods and cones have died include injection of stem cells to regenerate the rods and cones; "optogenetics," a type of gene therapy where a photoreceptor gene is inserted into blind neurons to make them sensitive to light; and installation of electronic prosthetic devices, such as a small light-sensitive retinal chip with electrodes that stimulate blind neurons.

Eight years ago, Kramer, Trauner, a former UC Berkeley chemist now at the University of Munich, and their colleagues developed an optogenetic technique to chemically alter potassium ion channels in blind neurons so that a photoswitch could latch on. Potassium channels normally open to turn a cell off, but with the attached photoswitch, they were opened when hit by ultraviolet light and closed when hit by green light, thereby activating and deactivating the neurons.

Subsequently, Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium channels without the need to genetically modify the channel.

Newer versions of AAQ now being tested have demonstrated better results, as per the researchers. They activate neurons for days rather than hours using blue-green light of moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is not needed to switch them off.

Source

Implanted neurons fuse with pre-existing brain wiring in the lab

Among the many hurdles to be cleared before human embryonic stem cells can achieve their therapeutic potential is determining whether or not transplanted cells can functionally integrate into target organs or tissues.

Writing in the Proceedings of the National Academy of Sciences (PNAS) , a team of Wisconsin scientists reports, in a study funded by the US National Institutes of Health, that neurons, forged in the lab from blank slate human embryonic stem cells and implanted into the brains of mice, can successfully fuse with the brain's wiring, and both send and receive signals.

Neurons are specialized, impulse conducting cells that are the most elementary functional unit of the central nervous system. The 100 billion or so neurons in the human brain are constantly sending and receiving the signals that govern everything from walking and talking to thinking. The work represents a crucial step toward deploying customized cells to repair damaged or diseased brains, the most complex human organ.

"The big question was can these cells integrate in a functional way," says Jason P. Weick, the lead author of the new study and a staff scientist at the University of Wisconsin-Madison's Waisman Center. "We show for the first time that these transplanted cells can both listen and talk to surrounding neurons of the adult brain."

The Wisconsin team tested the ability of their lab grown neurons to integrate into the brain's circuitry by transplanting the cells into the adult mouse hippocampus, a well-studied region of the brain that plays a key role in processing memory and spatial navigation. The capacity of the cells to integrate was observed in live tissue taken from the animals that received the cell transplants.

Weick and colleagues also reported that the human neurons adopted the rhythmic firing behavior of many brain cells talking to one another in unison. And, perhaps more importantly, that the human cells could modify the way the neural network behaved.

A critical tool that allowed the UW group to answer this question was a new technology known as optogenetics, where light, instead of electric current, is used to stimulate the activity of the neurons.

"Previously, we've been limited in how efficiently we could stimulate transplanted cells. Now we have a tool that allows us to specifically stimulate only the transplanted human cells, and lots of them at once in a non-invasive way," says Weick.

Weick explains that the capacity to modulate the implanted cells was a necessary step in determining the function of implanted cells because previous technologies were too imprecise and unreliable to accurately determine what transplanted neurons were doing.

Embryonic stem cells, and the closely related induced pluripotent stem cells can give rise to all of the 220 types of tissues in the human body, and have been directed in the lab to become many types of cells, including brain cells.

The appeal of human embryonic stem cells and induced pluripotent cells is the potential to manufacture limitless supplies of healthy, specialized cells to replace diseased or damaged cells. Brain disorders such as Parkinson's disease and amyotrophic lateral sclerosis, more widely known as Lou Gehrig's disease, are conditions that scientists think may be alleviated by using healthy lab grown cells to replace faulty ones. Multiple studies over the past decade have shown that both embryonic stem cells and induced cells can alleviate deficits of these disorders in animal models.

The new study opens the door to the potential for clinicians to deploy light-based stimulation technology to manipulate transplanted tissue and cells. "The marriage between stem cells and optogenetics has the potential to assist in the treatment of a number of debilitating neurodegenerative disorders," notes Su-Chun Zhang, a UW-Madison professor of neuroscience and an author of the new PNAS report. "You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light."

Source

Editorial note: Outcome from this research will have a major role to play in retinal diseases, since retina is considered to be a part of the brain, and most stem cell treatments have not been successful due to issues with connectivity of the newly formed retinal cells derived from stem cells, with the functional ones that preexist in the retina. 

FDA Requests More Trials of Retinal Disease Treatment

Alimera Sciences, Inc., a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, today announced that it has received a complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) in response to the New Drug Application (NDA) for ILUVIEN® for the treatment of diabetic macular edema (DME) associated with diabetic retinopathy.

A CRL is issued by the FDA's Center for Drug Evaluation and Research when their review of an application is completed and questions remain that precludes the approval of the NDA in its current form.

Alimera is seeking approval for Iluvien as a treatment for diabetic macular edema, a condition that can cause blurred vision and blindness.

The FDA stated that it was unable to approve ILUVIEN because there was no provide sufficient data to support that ILUVIEN is safe and effective in the treatment of patients with DME. The FDA stated that the risks of adverse reactions shown for ILUVIEN in the FAME® Study were significant and were not offset by the benefits demonstrated by ILUVIEN in these clinical trials. The FDA has indicated that Alimera will need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

The company officials will request a meeting with the FDA to clarify its next steps. 

ILUVIEN is Alimera's investigational, sustained drug delivery system that releases sub-microgram levels of fluocinolone acetonide (FAc) for the treatment of DME.

Alimera initially had asked the FDA to approve Iluvien in June 2010. In December, the FDA asked the company to report data from a third year of a clinical trial, and Alimera filed that data in May 2011. It also responded to the agency's concerns about manufacturing, packaging and sterilization of the drug. 

In December 2010, the FDA issued a CRL to Alimera related to its June 2010 NDA for ILUVIEN, which included data through month 24 of the FAME™ Study.

In that first CRL, the FDA asked for, among other things, analyses of the safety and efficacy data through month 36 of the FAME Study. Alimera submitted a response to the FDA on May 12, 2011, addressing the issues raised in the first CRL and including 36-month trial data. The FDA classified Alimera's response as a Class 2 resubmission, resulting in a six-month review period and a Prescription Drug User Fee Act, or PDUFA, date of November 12, 2011.

For Europe, Alimera expects to submit its formal response to the Preliminary Assessment Report to the Medicines and Healthcare products Regulatory Agency (MHRA) later this month. Based on this submission, the MHRA is expected to make a recommendation on the approvability of ILUVIEN to Alimera and the Concerned Member States (Austria, France, Germany, Italy, Portugal and Spain) by the end of this year, with a decision regarding the approval of ILUVIEN expected in the first half of 2012. The market opportunity in Europe is similar in size to the U.S. market opportunity.

Source

Success in clinical trial brings researchers closer to cure for blindness

Researchers at Hadassah Hospital in Israel, led by Dr. Eyal Banin, have completed a clinical trial that tested the use of gene therapy to restore sight to patients suffering from Leber's Congenital Amaurosis (LCA). Dana and Yossi, two participants in this study, suffer from Leber's Congenital Amaurosis (LCA), the most severe form of all inherited retinal dystrophies causing congenital blindness. Like others affected, they have experienced severe visual impairment since birth. LCA sufferers experience poor night vision, low visual acuity and a constricted visual field. This low vision continues to deteriorate, leading to total blindness. Other symptoms may include crossed eyes, roving eye movements, unusual sensitivity to light, and/or cataracts. LCA is usually inherited as an autosomal recessive genetic condition. Those with LCA suffer in darkness, without sight and without hope. Until now.

Dr. Eyal Banin, MD, Ph.D., at the Center for Retinal and Macular Degeneration at Hadassah University Medical Center, in collaboration with leading researchers in the United States and Great Britain, performed a clinical trial that has successfully demonstrated the efficacy of gene therapy in the treatment of LCA.  LCA is caused by a mutation in the RPE65 gene.  In this clinical trial, a normal RPE65 gene was injected into the retina to replace the damaged gene and renew protein production. Participants Dana and Yossi were treated with this gene therapy in just part of the retina of one eye, with dramatic results. Shortly after treatment, both participants noted a substantial improvement in their vision.

When asked about the results of this treatment, Yossi said, "I felt the real change, the real revolution, after 21 days. It was amazing because today I see things that I have never seen before. I'm very proud to be a part of this research." Dana said, "Learning of new treatment was a life-changing event. I'm experiencing a real change. I was surprised to see real improvement in my vision."

Yossi and Dana's self-reporting of visual improvement is corroborated by objective, quantitative measurements of the treated area that also show significant improvement. With the continuation of this research, these scientists will be able to develop gene therapy to treat additional retinal degeneration diseases and make it possible to treat many more patients.

To watch a just-released video with more information about this clinical trial, its researchers and study participants, please visit http://www.mvrf.org/news.php.

Dr. Banin says: "You cannot imagine what an effect this has had not only on the treated patients, their families and on us, but also on the wider population of patients with retinal and macular degenerations here in Israel, who suddenly feel some glimmer of hope.."

Keith A. Lampman, Executive Director of MVRF, says, "We are extremely excited about the results of this study and feel confident that, in close collaboration with our partners across the globe, we are closer than ever to a cure for retinal diseases."

Source & Source

First patient receives novel gene therapy for a type of blindness

The first patient to receive gene therapy for an incurable type of blindness was treated at the John Radcliffe Hospital in Oxford this week as part of a trial led by Oxford University.

If successful, the advance could lead to the first-ever treatment for choroideraemia, a progressive form of genetic blindness that first arises in childhood and is estimated to affect over 100,000 people worldwide.

‘This disease has been recognised as an incurable form of blindness since it was first described over a hundred years ago. I cannot describe the excitement in thinking that we have designed a genetic treatment that could potentially stop it in its tracks with one single injection,’ says Professor Robert MacLaren of the University of Oxford, who is leading the trial.

Jonathan Wyatt, 63, an arbitration lawyer from Bristol had the surgery at the Oxford Eye Hospital based at the John Radcliffe – the main NHS centre for this trial. He is the first of 12 people in this initial human trial that will receive the novel gene therapy. Mr Wyatt was diagnosed with choroideraemia in his late teens and has suffered progressive sight loss ever since. He now sees only blackness except for a small area of a few degrees in diameter in the centre of his vision.

Choroideraemia is a genetic disease that leads to progressive degeneration of the retina in the eye. It generally affects males only and there is no treatment. The diagnosis is usually made in childhood and leads to blindness in men by their forties. It occurs due to deficiency of the REP1 gene located on the X chromosome.

The novel gene treatment was developed by Professor MacLaren at Oxford University, in collaboration with Professor Miguel Seabra at Imperial College, London. It is designed to provide the gene missing in people with choroideraemia to stop the deterioration that gradually leads to blindness.

It uses a virus essentially as a delivery vehicle that ferries DNA including the missing gene into the right part of the eye. The virus has been engineered to infect the light-sensitive cells in the retina known as photoreceptors. There the gene is switched on and becomes active.

With this particular gene therapy, the treatment could provide a one-off permanent correction of the disease because the gene is thought to remain in the retinal cells indefinitely.

‘This trial represents the world’s first ever attempt to treat this disease and the first time that gene therapy has been directed towards the light-sensitive photoreceptor cells of the human retina,’ says Professor MacLaren. ‘This represents a major breakthrough and is highly significant for patients who are losing sight from other photoreceptor diseases, such as retinitis pigmentosa.’

The trial will see 12 patients undergo surgery in which the gene therapy is injected into one eye. The other eye would then act as a control against which to assess any treatment effect. The researchers would however aim to go on to treat the second eye, should the treatment be proven to be effective.

The aim of the trial is primarily to assess safety, but it will also gain initial data on how effective the treatment is. The researchers estimate that it will take two years to know whether or not the degeneration has been stopped completely by the gene therapy.

‘While safety appears so far to be fine, the efficacy of the gene therapy will only be evident after 24 months. We need this time to measure any effect as the degeneration caused by choroideraemia is slow,’ explains Professor MacLaren, who is also an honorary consultant at the Oxford Eye Hospital and Moorfields Eye Hospital.

The clinical trial is funded by a grant awarded to the University of Oxford by the Health Innovation Challenge Fund – a translational award scheme funded jointly by the Wellcome Trust and the Department of Health.

Professor Seabra, who played a key role at Imperial College London in identifying the gene causing choroideraemia and in eliciting the mechanism of cell death in the retina, comments: ‘The ability to offer a gene replacement treatment for these patients was the final objective of 20 years of intense research in my laboratory. This is a moment of fulfilment for us and a dream come true for all choroideraemia patients.’

Source

Age-related Macular Degeneration (AMD) may now be less common than in the past

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in persons over 65 years of age, a group that is growing in numbers because of increased life expectancy.  AMD affects the center of the retina, the macula, where collection of fluid, fatty deposits, pigmentary changes, and blood, may cause significant visual impairment in about 10% of patients affected by ‘wet’ AMD. The rest 90% suffer from the non-progressive type of AMD, referred to as ‘dry’ AMD, where the features do not progress, and the vision largely remains stable, or deteriorates slowly.

AMD was considered to be more common in the Caucasian (or white) population, though recent studies from India indicate that the prevalence in India may be almost equal to the western population.

In the west, the prevalence was considered to be about 9.4 percent of US patients, based on a 1988-1994 Third National Health and Nutrition Examination Survey. But a recent study indicates the prevalence to be 6.5 percent in patients aged 40 and older, lower than the 9.4 percent reported earlier.

The new study involved 5,533 US adults, aged 40 years of older, who participated in the 2005-2008 National Health and Nutrition Examination Survey. Based on the digital photographs taken of both eyes, the researchers found that 6.5 percent of the participants had signs of some level of AMD, including tiny yellow or white deposits in the retina, pigment changes and deterioration of the retina and surrounding tissue. Less than one percent had the ‘wet’ disease, the advanced stage in which eyesight is more severely affected.

Extrapolating these new figures, an estimated 7.2 million people in the U.S. having any degree of AMD, with about 890,000 of these with advanced ‘wet’ disease. If that rate was correct and remained unchanged, it would mean about 18 million Americans should demonstrate signs of AMD. The new estimates represent a reduction of more than 30 percent in rates of AMD. The reasons for such a decrease in numbers is not very clear. The researchers feel it could reflect changes in time in smoking, diet and use of medications (anti-oxidant vitamins and zinc). A better understanding of the reduction of AMD in older population could help point to new prevention strategies that could lead to further reduction in numbers.

If we extrapolate the same percentage to Indian population, as some studies have indicated that the prevalence of AMD in Indian patients matches those of the western world, we have about 65 million patients in India. 

Source: Archives of Ophthalmology Jan 2011. Click here for the paper.

New treatments for Age-related Macular Degeneration and Stargardt's disease

Elderly people losing their vision from age-related macular degeneration might one day have a treatment option that requires fewer injections into the eye than the standard drug now used.

In testing, an experimental drug being developed by Regeneron Pharmaceuticals, when injected every eight weeks, proved as effective as the standard treatment, Lucentis from Genentech, which was injected every four weeks. The findings are from two clinical trials that Regeneron is expected to announce on Monday.

In a separate development, Advanced Cell Technology is expected to announce Monday that it has won regulatory approval to test a therapy derived from human embryonic stem cells in people with Stargardt’s macular dystrophy, another retina disease.

It is only the second trial of a therapy derived from human embryonic stem cells to be cleared by the Food and Drug Administration. The first involves a treatment for spinal cord injury developed by Geron.

Age-related macular degeneration is the leading cause of blindness in the elderly. Lucentis can restore a person’s ability to drive and read, in some cases.

But the drug works best when given every four weeks, which can be inconvenient for patients and doctors. Doctors often give Lucentis less frequently, but even if that regimen produces good results, patients must still get checkups every month to make sure their vision is not deteriorating.

Regeneron’s drug, which is called VEGF Trap-Eye, “gives us the opportunity to not have to see them monthly,” said Dr. Jeffrey Heier of Boston, an investigator in one of the trials and a consultant to Regeneron. That would be “very meaningful to patients and their families,” he said.

Regeneron and its partner, Bayer, said they planned to apply for approval of the drug in the first half of 2011.

The two similar trials involved a total of 2,457 patients who were randomly chosen to receive either Lucentis every four weeks or VEGF Trap-Eye either every four weeks or every eight weeks. In the eight-week arm, the first three doses were given every four weeks.

After a year, roughly 95 percent of the patients in all the arms of the trial maintained their vision, meaning their ability to read an eye chart declined by no more than 15 letters, or three lines.

VEGF Trap-Eye was also “noninferior” to Lucentis in terms of the average change in vision after one year. Lucentis recipients had a mean gain of 8.1 letters and 9.4 letters in the two trials. Those getting Regeneron’s drug every eight weeks had gains of 7.9 letters and 8.9 letters. Regeneron said the two drugs were equally safe.

Both VEGF Trap-Eye and Lucentis block a protein called vascular endothelial growth factor that causes blood vessels to grow and leak into the eye.

VEGF Trap-Eye could become the first big product for Regeneron, which was founded in 1988 and is based in Tarrytown, N.Y. It sells one drug for a rare disease and has garnered hundreds of millions of dollars from licensing deals with big pharmaceutical companies.

Regeneron’s drug is likely to face competition from off-label use of Genentech’s cancer drug Avastin. When used in the eye, Avastin costs about $50 a dose, compared with about $2,000 for Lucentis. Still, even with such low-priced competition, Lucentis has sales exceeding $2 billion globally.

Meanwhile, Advanced Cell Technology, of Marlborough, Mass., said it would test its stem cell therapy on 12 adults with severe vision loss caused by Stargardt’s, an inherited disease.

The company has turned human embryonic stem cells into retinal pigment epithelial cells, which will be surgically implanted into the eye. The hope is that the implanted cells will replace those injured by the disease.

Human embryonic stem cells are controversial because their creation usually entails the destruction of human embryos, although Advanced Cell Technology is working on a technique to avoid that.

Embryonic cells can also form tumors if injected into the body. Dr. Robert Lanza, chief scientist at Advanced Cell, said the company had to prove to the F.D.A. that its retinal cells contained virtually no residual embryonic stem cells. It took a year for the company to get clearance for the trial from the F.D.A.

It is likely to be several years before such a treatment can reach the market, if it works. Still, even starting the trial could be a boost to Advanced Cell, which often makes headlines but has struggled to raise money. Its shares closed at 5 cents on Friday.

Dr. Peter J. Francis, an associate professor at the Oregon Health and Science University, which will be a site for the trial, says the eye is a good place to test stem cell therapy because it is accessible. Also, he said, there is less chance of rejection of the implanted cells because the eye is shielded somewhat from the body’s immune system.

There is no treatment for Stargardt’s, which affects more than 25,000 people in the United States (and about 1 lakh people in India). The disease is usually diagnosed during childhood and it causes a loss of central vision, though not usually peripheral vision.

From the New York Times

Note from Retina India:
Retina India is creating registries or databases of patients with macular degeneration and Stargardt's disease. If you, or someone you know has the above diseases, or any other retinal disease, please write to info@retinaindia.org to be included in the database. Retina India also runs Connect Programs, which allow patients and family members interested in one particular diseases (e.g. Stargardt Connect) to connect with each other, which allows them to discuss and resolve their problems.

Treating colour blindness with Gene Therapy

Recent research has demonstrated that colour blindness may be capable of rescue by a simple sub-retinal injection of the genetic sequence for the missing photopigment. A research team, based at the University of Washington, have comprehensively shown that animals, previously documented to be colour-blind, are capable of colour discrimination within 20 weeks of treatment. The research not only adds optimism to the field of gene therapy for many other retinal disorders but also suggests an encouraging level of plasticity in how the brain manages new information.

Colour vision
Colour vision is both a fascinating and complex process. Fascinating because interpretation of the world around us through the capacity of colour vision almost defines the "human" experience; complex because the "sensation" of colour and fine acuity vision involves an array of highly differentiated and specialised cell types communicating with the cerebral cortex to create an output that continues to elude our detailed understanding.

To understand how an eye sees colour, click here.

The wavelengths of light visible to the human eye range between approximately 400nM and 700nM allowing humans to distinguish over a million different colours. This impressive feat is achieved through the processing of signals from three types of cone photoreceptor distinguished by their sensitivity to varying wavelengths: "S" (short) with a maximal sensitivity at about 430nM; "M" (medium) with a maximal sensitivity at about 530nM and finally; "L" (long) with a maximal sensitivity at about 560nM. The sensitivities however, accommodate broad "tuning" capabilities such that each type can respond to wavelengths across the visible light spectrum. The sensitivity of any particular photoreceptors are determined by the type of opsin expressed which, in turn, is determined by the sequence of amino acids that make up an opsin protein. Changes in the sequence of amino acids can change the spectral sensitivity for example, changes in 2 out of the approximate 350 amino acids in the L- and M- opsins in humans account for most of the 30nm difference in their peak wavelength sensitivities. Red-green colour blindness is a condition brought about through a disruption of either the long L- or the middle M- wavelength sensitive visual photopigments found in cone photoreceptors. Although the condition has been recognised and studied for over 200 years, the present research is the first report on the use of genetic technology to correct a deficit of colour vision in a mammalian species.

Colour blindness
Red-green colour blindness is among the most common genetic disorders found in humans. The incidence is known to vary with ethnicity (about 8% in Caucasian men, 4% in Japanese men and 3% in African men, and about 6-8% in Indians).

To understand how colour blindness affects sight, click here.

As the L- and M- wavelength sensitive visual photopigment genes ("OPN1LW"-opsin 1 long wave sensitive and "OPN1MW"-opsin 1 medium wave sensitive) are found concatenated head-to-tail along the X chromosome, this in part explains why the condition affects 3-8% of males but only 1% of females. Heterozygous carrier females are estimated at about 15% of the Caucasian population. In their research into correcting the colour deficit the University of Washington research team chose the New World squirrel monkey (Saimiri sciureus) as an experimental model. All male and some female squirrel monkeys are colour-blind "dichromats" (the three different types of cone photoreceptor make humans "trichromatic" whereas most other mammals in the animal kingdom have only two types of cone and are referred to as "dichromatic"). Dichromatic squirrel monkeys have S- cones and M- cones and the idea to deliver the L- photopigment gene sequence would allow the researchers, if successful, to demonstrate a change from dichromatic to trichromatic vision.

Insightful research
The research, led by Professors Jay and Maureen Neitz, was aimed not so much at developing a gene based therapeutic for the treatment of human colour blindness but more to demonstrate the principle of gene therapy for correcting a genetic fault in the retina. While the technology could be developed further and used to treat the condition in humans, it is likely that regulatory authorities would prefer to observe the use of gene therapy for more severe ocular disorders before approving such technology for use in an otherwise healthy retina.

The research group genetically engineered a copy of the human L-opsin gene (OPN1LW) under the control of the L/M opsin enhancer and promoter and packaged the transcript into the recombinant adeno-associated viral (AAV) genome (serotype 2, capsid 5). High-titre infectious particles were prepared and injected in batches of 100uL. Genetic regulatory elements were chosen to direct expression in M- rather than S- cones. Researchers treated colour-blind adult squirrel monkeys, colour blind from birth, with three sequential sub-retinal injections in different areas of the retina, each injection comprising a volume of approximately 100uL and in total containing an estimated 2.7 X 1013 virus particles. Prior to treatment, animals were trained to perform a computer based colour vision test (the Cambridge Colour Test) and control baseline results were built up from over a year's worth of testing.

Twenty weeks after administration, the results clearly demonstrated a change in the spectral sensitivity of a subset of the cone cell population as detected using a custom built wide-field colour multifocal electroretinogram system (mf-ERG). Following treatment, animals tested on the Cambridge Colour Test showed an improved threshold for blue-green and red-violet wavelengths and this improvement coincided with robust levels of transgenic gene expression previously reported for similarly treated squirrel monkeys. In short, the animals had gained trichromatic vision as soon as the new gene was producing opsin protein. So far the researchers have reported that the improvement in colour vision in treated animals has remained stable for more than 2 years. Plans are scheduled to continue testing to allow for long-term evaluation of the technology.

Teaching old monkeys new tricks
The signals for colour are processed through post-receptoral cells in the retina and brain and part of the processing includes computations in specific ganglion cells that subtract the signals received from different types of cone photoreceptor. Such computation, it was thought, develops specifically from birth contingent on the number and types of photoreceptors present. Adding a "new" signal to an established system was thought unlikely to work as the established system would not have developed the pathway required for that particular signal type. The current research from the University of Washington has changed that idea. As soon as the new photopigment is expressed in the retina, there is a simultaneous ability to process new wavelengths of light. Previously dichromatic monkeys acquired the capability for performing tasks of colour discrimination as proficiently as trichromats. This suggests a level of plasticity previously thought to be unlikely. Neural connections, it was thought, established during development would be unlikely to efficiently process "new inputs" (such as that delivered by the gene therapy). As both Prof. Jay and Maureen Neitz comment, "classic visual deprivation experiments [dating back to the 1960s] have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young". Cleary the results from the recent research suggest otherwise and the observations, reported in the journal Nature (Vol. 461, pp784-788), provide encouragement that gene delivery to the eye in the context of adult onset diseases may have a real prospect of success.

Next steps
The team are now looking at another retinal disorder - achromatopsia - and are planning to restore the missing or defective photoreceptor components to the healthy retina and thereby treat the disease in humans. Achomatopsia, meaning "without colour", is a disorder in which the individual is unable to distinguish colour due to a deficient cone mediated eletroretinogram and typically sufferers will have a severely compromised visual acuity. Approximately 1 in 30,000 individuals are affected by the disorder that can cause permanent central vision loss and for which no effective medical therapies exist. The University of Washington team is now testing a gene therapy approach in a mouse model of achromatopsia in an effort to reproduce the success demonstrated in the correction of colour-blindness.

- From Euretina

Welcome to Retina India

Retina India is a not-for-profit organization, registered with the Charity Commissioner, Mumbai, India, established for empowering people with retinal disorders, and bringing them and their families on a common platform with physicians, researchers, counselors, low vision and mobility experts and other specialists.

Why do we need another not-for-profit organization?

India is home to approximately 24 million blind people, the largest in the world. Additionally, there are another 52 million visually impaired in the country. It is thought that if this trend is allowed to continue, the number of blind people would increase to 31.6 million by 2020.

The blindness-prevention programs that are sponsored by governmental agencies and by non governmental organizations (NGOs) usually focus on "avoidable" or "preventable" blindness that commonly includes cataract and corneal problems. Even though patients with preventable blindness in India are significant, the prevalence of retinal ailments, such as retinitis pigmentosa and allied disorders, macular degeneration, diabetic retinopathy, etc. is gradually increasing. Some of these diseases do not even have a cure at this time, and usually leave the affected people with permanent visual impairment for a lifetime. There has been no singular effort in India to unite the efforts in the fields of medical research, education, rehabilitation and welfare of people with retinal disorders.

It is this void that Retina India aims to fill.

Retina India is focused on spreading awareness amongst society, the NGOs and the Governmental agencies about people with retinal ailments and the specific issues they and their families face. We also wish to help them make a difference to their own lives, and to the lives of people around them.

Our Vision

To empower patients and families of patients with retinal ailments, and help them make a significant contribution to their own lives, and to the lives of people around them.

Our Mission

To increase awareness of retinal diseases and champion the cause of people who get affected by them, and to induce increased research efforts towards treatment for such diseases.
Our people

Simply said, Retina India is a movement, It is a movement that includes all of you. It is our strong belief that when people come together, and work towards a common cause, a lot can get done.

Retina India includes patients with retinal disorders and their families. It also includes retinal specialists and other ophthalmologists with an interest in retinal diseases, low vision experts, mobility experts, counselors, and others. We invite people with a social spirit, who have an inherent desire to do something good for others, and make a difference in someone's life, to volunteer and be a part of this movement. We also invite young adults, school and college students, to gain experience in working on a project for Retina India .

Our Key Objectives:

Patient Alliance: The alliance brings together patients with retinal disorders, along with their families and friends, to work for mutual benefit.

Medical Research and Treatments: Retina India highlights, coordinates and sponsors research in retinal treatment in India, while also informing the patients and their families about the current on-going research in India and around the world.

Clinical trials in India: We act as a channel to bring new treatments and technologies to India (Gene Therapy, Artificial Retina, Stem-Cell treatment, etc.) for Indian patients with retinal disorders.

Patient Registry: Retina India maintains databases (or registries) of patients with specific retinal diseases. Such registries will help inform patients likely to benefit from new treatments, such that they are not left to wonder whether a new treatment is beneficial to them or not, and in the process, spend a lot of time, effort and money in finding that out. Registries for Retinitis Pigmentosa, Macular Degeneration, Retinopathy of Prematurity, Leber's Congenital Amaurosis, etc. are already functional.

Education, Counseling & Advocacy: Activities range from encouraging beneficiaries to pursue their lives productively, counseling them about education, employment, marriage and family issues, to rehabilitation, independence training and mobility skills via associations with other organizations in the country. We are also commited to advocacy about the concerns of people with retinal ailments.

We welcome you to make a difference in your own life, and in the lives of people around you.