EYLEA (aflibercept) injection receives FDA breakthrough therapy designation for diabetic retinopathy in patients with diabetic macular edema

Regeneron Pharmaceuticals, Inc. has announced that the U.S. Food and Drug Administration (FDA) has granted Eylea® (aflibercept) injection a breakthrough therapy designation for the treatment of diabetic retinopathy in patients with diabetic macular edema (DME). The designation is based on positive results in two Phase 3 trials (VIVID-DME and VISTA-DME), in which Eylea demonstrated a statistically significant improvement
in a pre-specified measure of diabetic retinopathy in patients with DME after two years of treatment.

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).

Launch of a new alliance for global assessment of diabetic retinopathy

A new project has been launched to assess the awareness, treatment and implications of diabetic retinopathy globally. Results are intended to inform decision-making and policy development around this common and serious complication of diabetes.

Project partners, the International Federation on Ageing (IFA) and the International Diabetes Federation (IDF), working in collaboration with the New York Academy of Medicine (NYAM) and the International Agency for the Prevention of Blindness (IAPB) will gather evidence on knowledge, policies, standards of care, and supportive services for retinopathy across 40 countries.

Retinopathy is one of the most common complications associated with diabetes and one of the major causes of adult blindness. Up to 11% of adults with diabetes have Diabetic Macular Edema (DME), a specific type of diabetic retinopathy. According to the IDF Diabetes Atlas 6^th edition, there are large variations in the estimates of retinopathy prevalence in people with known diabetes, with estimates ranging from 11 to 45% worldwide in people with type 1 and type 2 diabetes.

The global assessment of retinopathy has two substantive and connected phases:

1. Phase I comprises approximately 120 interviews in eight countries representative of low, middle and high socio-economic status to better understand the level of awareness of: retinopathy as a condition and common complication of diabetes; the access, availability and pathway to retinopathy services; and the existence and content of relevant governmental policy.

2. Phase II is the implementation of a survey in 40 countries, which will be formulated based on the data gathered in Phase I. The survey aims to garner statistically significant evidence intended to assist in the development of effective governmental policy.

The project will culminate in the production of a barometer report and a compendium of resources designed to increase awareness, as well as to inform policy and practice related to diabetic retinopathy and vision loss across countries.

This project is financially supported by Bayer Pharma AG. Bayer is not involved in the analysis of the findings.

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Notal Vision's ForeseeHome AMD Monitor receives FDA clearance

Notal Vision's ForeseeHome™ AMD Monitor has received Section 510 (k) clearance from the U.S. Food and Drug Administration (FDA).

The ForeseeHome AMD Monitor is the first ophthalmic device linking patients and doctors between eye exams for ongoing monitoring of age-related macular degeneration (AMD). 

Patients complete a frequent but brief exam on their ForeseeHome AMD Monitor, in the comfort of their own home, and data is transmitted to the patients' eye care physician and the Notal Vision Data Monitoring Center.  The award winning ergonomic design of the ForeseeHome AMD Monitor is comfortable and easy to use for patients at risk of vision loss from wet AMD.

Wet AMD is the leading cause of blindness in people over the age of 60 in the western world. Recent breakthroughs in treatments place even greater importance on early detection, which can reduce the risks of vision loss associated with wet AMD.  Frequent monitoring is critical in detecting disease onset as early as possible and the ForeseeHome AMD Monitor is the first home monitoring device for following patients at risk of vision loss, offering hope for early intervention through early detection.

Numerous clinical studies have demonstrated the ForeseeHome AMD Monitor is an accurate and reliable tool for frequent monitoring of patients at risk for vision loss from wet AMD.

FDA Indication for Use: 

ForeseeHome is intended for use in the detection and characterization of central and paracentral metamorphopsia (visual distortion) in patients with age-related macular degeneration as an aid in monitoring progression of disease factors causing metamorphopsia including, but not limited to choroidal neovascularization (CNV). It is intended to be used at home for patients with stable fixation. ForeseeHome is not intended to diagnose; diagnosis is the responsibility of the prescribing eye-care professional.

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Ohr Pharmaceutical initiates Investigator sponsored trial of squalamine eye drops in diabetic macular edema

Ohr Pharmaceutical, Inc., a research and development company with a primary focus in ophthalmology, has announced the initiation of a Phase II investigator sponsored clinical trial, OHR-005, testing Squalamine eye drops in patients with diabetic macular edema (DME).

The current standards of care for DME include chronic treatments of VEGF inhibitors administered directly into the eye via an injection. Squalamine eye drops may potentially represent a less-invasive treatment option for patients suffering from diabetic macular edema, as per the investigators of this trial. 

OHR-005 is a randomized, placebo controlled, investigator sponsored, multicenter Phase II clinical trial evaluating the effect of Squalamine Eye Drops in patients with DME. The primary endpoints will measure change in retinal thickness and change in Best Corrected Visual Acuity (BCVA) over 24 weeks. Secondary objectives include additional BCVA measurements, change in foveal thickness, evaluation of the need for rescue injections of ranibizumab (Lucentis®) and an assessment of the safety and tolerability of Squalamine Eye Drops. The trial is designed to enroll up to 30 subjects at 3 sites in the United States. Patients will be randomized to receive a single injection of ranibizumab at baseline followed by treatment with either Squalamine lactate ophthalmic solution 0.2% or placebo ophthalmic solution, administered QID for 24 weeks.

Squalamine is an anti-angiogenic small molecule with a novel intracellular mechanism of action, which counteracts multiple growth factors implicated in the angiogenesis process. Ohr Pharmaceutical has developed a novel eye drop formulation of Squalamine for the treatment of wet-AMD, designed for self-administration, which may provide several potential advantages over the FDA approved current standards of care, which require intravitreal injections directly into the eye. The drug, using an intravenous administration in over 250 patients in Phase I and Phase II trials for the treatment of wet-AMD, showed favorable biological effect and maintained and improved visual acuity outcomes. In May 2012, the Squalamine Eye Drop program was granted Fast Track Designation by the FDA. A Phase II randomized, double blind, placebo-controlled study (OHR-002) to evaluate the efficacy and safety of Squalamine Eye Drops for the treatment of wet-AMD has completed enrolling patients. Three additional investigator sponsored trials (IST) are evaluating Squalamine eye drops for the treatment of proliferative diabetic retinopathy, retinal vein occlusion and diabetic macular edema, with one additional IST expected to be initiated in diabetic macular edema in the second calendar quarter of 2014.

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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.

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.

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FDA approves Eylea for patients with Age-related Macular Degeneration

Regeneron Pharmaceuticals, Inc. has announced that the U.S. Food and Drug Administration (FDA) has approved Eylea (aflibercept) Injection, known in the scientific literature as VEGF Trap-Eye, for the treatment of patients with neovascular (wet) Age-related Macular Degeneration (AMD) at a recommended dose of 2 milligrams (mg) every four weeks (monthly) for the first 12 weeks, followed by 2 mg every eight weeks (2 months).

The approval of Eylea was granted under a Priority Review, a designation that is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists.  This approval was based upon the results of two Phase 3 clinical studies.  In these studies, Eylea dosed every eight weeks, following three initial monthly injections, was clinically equivalent to the standard of care, Lucentis® (ranibizumab injection) dosed every four weeks, as measured by the primary endpoint of maintenance of visual acuity (less than 15 letters of vision loss on an eye chart) over 52 weeks.  The most common adverse reactions (frequency of 5% or more) reported in patients receiving Eylea were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.  The adverse event profile was similar to that seen with ranibizumab.

As per the experts, Eylea offers the potential of achieving the efficacy that the ophthalmic world had come to expect from the current anti-VEGF agents, but with less frequent injections and no monitoring requirements. This, as per these experts, may reduce the need for costly and time-consuming monthly office visits for patients and their caregivers.

About Eylea™ (aflibercept) Injection:

Vascular Endothelial Growth Factor (VEGF) is a naturally occurring protein in the body.  Its normal role in a healthy organism is to trigger formation of new blood vessels (angiogenesis) supporting the growth of the body's tissues and organs.  However, in certain diseases, such as wet age-related macular degeneration, it is also associated with the growth of abnormal new blood vessels in the eye, which exhibit abnormal increased permeability that leads to edema. Scarring and loss of fine-resolution central vision often results.  

Eylea, known in the scientific literature as VEGF Trap-Eye, is a recombinant fusion protein, consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and formulated as an iso-osmotic solution for intravitreal administration.  Eylea acts as a soluble decoy receptor that binds VEGF-A and placental growth factor (PlGF) and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Eylea is indicated for the treatment of patients with neovascular age-related macular degeneration (wet AMD).  Eylea is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients in EYLEA.

The recommended dose for Eylea is 2 mg administered by intravitreal injection every four weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once every eight weeks (2 months).  Although Eylea may be dosed as frequently as 2 mg every four weeks (monthly), additional efficacy was not demonstrated when Eylea was dosed every four weeks compared to every eight weeks.

There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF inhibitors, including Eylea, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).  The incidence of ATEs with Eylea in clinical trials was low (1.8%).

Serious adverse reactions related to the injection procedure have occurred in less than 0.1% of intravitreal injections with Eylea and include endophthalmitis, traumatic cataract, and increased intraocular pressure.

About the VIEW 1 and VIEW 2 Clinical Studies:

The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD.  A total of 2412 patients were treated and evaluable for efficacy (1817 with Eylea) in the two studies (VIEW 1 and VIEW 2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to one of four dosing regimens: 1) Eylea administered 2 mg every eight weeks following three initial monthly doses Eylea 2Q8); 2) Eylea administered 2 mg every four weeks Eylea 2Q4); 3) Eylea 0.5 mg administered every four weeks Eylea 0.5Q4); and 4) ranibizumab administered 0.5 mg every four weeks (ranibizumab 0.5Q4).  Patient ages ranged from 49 to 99 years with a mean of 76 years.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline.  Data are available through week 52.  Both the Eylea™ (aflibercept) Injection 2Q8 and 2Q4 dosing groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5Q4 group for the primary endpoint.

Select results of the VIEW 1 and VIEW 2 studies as described in the full Prescribing Information for the Eylea 2 mg every four weeks and Eylea 2 mg every eight weeks dosing groups as compared to ranibizumab dosed monthly group are shown below.

To check the efficacy outcomes at week 52 in VIEW 1 and VIEW 2 Studies, please click on the source below. 

Safety of Eylea:

Eylea™ (aflibercept) Injection is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients in Eylea.

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis and retinal detachments.  Proper aseptic injection technique must always be used when administering EYLEA.  Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with Eylea.  Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors.  Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately. There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF inhibitors, including Eylea, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).  The incidence of ATEs with Eylea in clinical trials was low (1.8%). Serious adverse reactions related to the injection procedure have occurred in less than 0.1% of intravitreal injections with Eylea including endophthalmitis, traumatic cataract, and increased intraocular pressure. The most common adverse reactions (greater than or equal to 5%) reported in patients receiving Eylea were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.

To see the full prescribing Information for Eylea, please click here.

Regeneron is collaborating with Bayer HealthCare on the global development of Eylea.  Bayer submitted an application for marketing authorization in Europe for wet AMD in June 2011.

Bayer HealthCare will market Eylea outside the United States, where the companies will share equally the profits from any future sales of Eylea.  Regeneron maintains exclusive rights to Eylea in the United States.

Source

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

Development of new stem cell treatment for retinal diseases

The company ReNeuron has announced that it has signed a patent and know-how license agreement with Schepens Eye Research Institute, Boston, USA, regarding the Company’s ReN003 stem cell therapy programme focused on diseases of the retina.

An affiliate of Harvard Medical School, Schepens recently announced that it is to join forces with the MassachusettsEye and Ear Infirmary in Boston to create the world’s largest pre-clinical and clinical ophthalmology research centre.  ReNeuron has been collaborating with Schepens in the early development of its human retinal precursor cells (hRPCs).  Based on the successful results of this initial collaboration, the Company has, through this license agreement, secured the relevant intellectual property rights to develop and commercialise its hRPCs in the field of human retinal stem cell therapeutics.  ReNeuron will continue to collaborate closely with lead Investigator Dr Michael Young and his team at Schepens to take the Company’s ReN003 programme through late pre-clinical development and into an initial clinical trial in the US in patients suffering from retinitis pigmentosa, a blindness-causing disease caused by degeneration of the photoreceptor cells in the retina. 

Researchers at Schepens have already published data describing the ability of the hRPCs to integrate with host retinal tissue in rodent models of damaged retina and differentiate into the light-sensitive rod cells found in healthy retina.  Subsequently, a novel and highly efficient proprietary cell expansion process has recently been optimised which does not involve genetic modification or other similar manipulation of the hRPCs.  This expansion technology is currently being employed by ReNeuron to grow and bank clinical-grade hRPCs to the quantities required for future clinical studies.  

Subject to regulatory advice and the results of IND-enabling late pre-clinical studies, the ReN003 programme is expected to enter its clinical phase in approximately 18 months.  Importantly, although retinitis pigmentosa is the initial target disease, the hRPCs developed in the programme will almost certainly be applicable as cell therapy candidates for other blindness-causing diseases, such as age-related macular degeneration and diabetic retinopathy. 

Schepens Eye Research Institute fights blindness by developing new technologies, therapies and knowledge to preserve and restore vision. Through a continuum of discovery, the Institute works toward a future in which blindness is prevented, alleviated, and, ultimately, cured.

Founded in 1950 by famed retinal surgeon Charles L. Schepens, M.D., Schepens Eye Research Institute is the largest independent eye research institute in the United States and an affiliate of Harvard Medical School. Since its inception, the Institute has trained more than 600 postdoctoral fellows in various disciplines of eye research; trained more than 500 eye surgeons who now practice around the world; and published more than 4,600 scientific papers and books about health and eye disease.

About ReNeuron:

ReNeuron is a leading, clinical-stage stem cell business.  Its primary objective is the development of novel stem cell therapies targeting areas of significant unmet or poorly met medical need.  

ReNeuron has used its unique stem cell technologies to develop cell-based therapies for significant disease conditions where the cells can be readily administered “off-the-shelf” to any eligible patient without the need for additional immunosuppressive drug treatments.  ReNeuron’s lead candidate is its ReN001 stem cell therapy for the treatment of patients left disabled by the effects of a stroke. This therapy is currently in clinical development.  ReNeuron’s ReN009 stem cell therapy is being developed as a treatment for peripheral arterial disease, a serious and common side-effect of diabetes. The Company is also developing stem cell therapies for other conditions such as blindness-causing diseases of the retina.

ReNeuron has also developed a range of stem cell lines for non-therapeutic applications – its ReNcell® products for use in academic and commercial research.  The Company’s ReNcell®CX and ReNcell®VM neural cell lines are marketed worldwide under license by USA-based Millipore Corporation.

Possible new treatment for Macular Degeneration

Researchers from University of Kentucky College of Medicine have identified an RNA-based mechanism in the retina that could be responsible for triggering the blindness associated with advanced dry age-related macular degeneration (AMD). The article has been published in Nature.

Unlike wet AMD, which results from scarring caused by leaky blood vessels and thus can be treated with a variety of angiogenesis inhibitors, dry AMD is initially characterized by the buildup of extracellular debris beneath the retina. Over time, those deposits cause significant atrophy of the retinal pigment epithelial (RPE) layer—a condition known as geographic atrophy—leading to loss of photoreceptors in the macula, the central and the most important part of the retina, which can ultimately advance to permanent blindness.

Although difficult to predict, dry AMD can turn into wet AMD at any time during disease progression. There are no medical or surgical treatments for dry AMD.

To find potential targets for geographic atrophy, Dr Jayakrishna Ambati and colleagues initially looked at levels of proteins and nucleic acids in eye samples from dry AMD patients. The researchers found that levels of the microRNA-processing enzyme dicer 1 ribonuclease type III (DICER1) were significantly lower in patient eyes than in non-AMD control eyes (p=0.0036). DICER1 levels were unchanged in the RPE layer of human eyes with other retinal diseases, suggesting that low DICER1 could be a specific marker of geographic atrophy.

The team next generated Dicer1 knockout mice to recapitulate the geographic atrophy phenotype in animals. All the Dicer1 knockouts showed degeneration of the RPE layer compared with wild-type littermate controls.

Subsequent studies in human RPE cells and mice revealed the specific mechanism by which low DICER1 levels led to degeneration of the RPE cells or layer, respectively. The decrease in DICER1 caused the accumulation of cytotoxic Alu RNA molecules in the RPE layer, where they caused degeneration of tissues making up the retina and macula.

Alu RNAs are retrotransposon sequences that exist throughout the human genome but do not code for proteins. Considered to be a toxic type of RNA that play a disease-causing role in a large section of the human genome, these Alu-related elements make up 11 percent of the human genome. They were considered "junk" DNA because researchers did not understand their role, but are now considered to play a crucial role in the death of retinal cells in those with geographic atrophy

In cultured human RPE cells with low DICER1 levels, antisense oligonucleotides targeting Alu RNA significantly blocked RPE cellular degeneration compared with control oligonucleotides (p<0.05).

Simply said, in patients with geographic atrophy, reduction of the Dicer enzyme in the retina leads to accumulation of Alu RNA, which leads to death of the retina.

The team has also developed two therapies that may prevent geographic atrophy. The first therapy increases Dicer levels in the retina by "over-expressing the enzyme", while the second therapy blocks Alu RNA with a drug that clings to the toxic structure and degrades it. Based on experiments performed in the laboratory, both therapies could efficiently prevent geographic atrophy.

The University of Kentucky has filed for patents on both therapies, and clinical trials are expected to begin by the end of this year.

Gene therapy shows promise against age-related macular degeneration

According to Tufts news, a gene therapy approach using a protein called CD59, or protectin, shows promise in slowing the signs of age-related macular degeneration (AMD). A new in vivo study conducted by researchers at Tufts University School of Medicine led by Rajendra Kumar-Singh, PhD, has demonstrated for the first time that CD59 delivered by a gene therapy approach significantly reduced the uncontrolled blood vessel growth and cell death typical of AMD,which is the most common cause of blindness in the elderly.

Activation of the complement system, a part of the immune system, is responsible for slowly killing cells in the back of the eye, leading to AMD. Activation of this system leads to the generation of pores or holes known as 'membrane attack complex' or MAC in cell membranes. CD59 is known to block the formation of MAC.

Previous studies using CD59 have have had limited success, as CD59 is considered to be unstable. By continuously producing CD59 in the eye. the approach by these investigators is able to overcome these barriers, which increases hope that it can be used to fight the progression of AMD as well as other diseases.

Kumar-Singh is associate professor in the department of ophthalmology at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Kumar-Singh and colleagues delivered CD59 to the eye using a deactivated virus similar to one previously shown to be safe in humans. Using an established mouse model of age-related macular degeneration, they found that eyes treated with CD59 had 62 percent less uncontrolled blood vessel growth and 52 percent less MAC than controls.

Source

For those who want to read the scientific article, please click here.

Abdominal obesity is a risk factor for AMD in middle aged men

Increasing weight in middle aged men could significantly increase the risk of blindness later in life, a study has found.

Melbourne University researchers, in a study that monitored changes in the waistlines of more than 21,000 men and women between 40 and 69 over several years, have noted that an expanding waistline puts men in danger of developing age-related macular degeneration (AMD), which is a leading cause of vision loss in the elderly. Even a small increase in waistline increases the risk of developing AMD. The researchers found that even for an increase of 0.1 in the waist/hip ratio, a man's chances of developing the disease soared by 75 per cent.

Women do not appear to be as affected as men, as found in this study, possibly due to pre-existing high levels of female hormone oestrogen acting as a preventive factor.

Digestion of abdominal fat releases oestrogen, which can cause inflammation in blood vessels at the back of the eyes. Such inflammation is considered to be one of the factors in developing AMD.

The disease is caused by the growth of new and abnormal blood vessels under the macula, a small oval-shaped area in the retina, which is an important part of the visual system in helping us see objects and print clearly. These abnormal blood vessels leak fluid, causing scar tissue to form and destroying vision in the centre of the eye. This makes it difficult to recognise faces, read or watch TV.

Around 90 per cent of cases develop dry AMD, a form of the disease which gradually progresses over many years, and for which there is no treatment currently. The rest of the cases develop wet AMD, which can progress fast and can quickly lead to blindness.

The current standard treatment involves monthly injections of agents, which can reduce the chances of developing the abnormal blood vessels, into the back of the eye. Given early enough, it can help to prevent complete loss of vision.

Research suggests eating healthy, with regular intake of fruit, vegetables and nuts in the diet, can reduce disease rates by up to 20 per cent. Also, eating chicken three times a week has been found to reduce the risk by half.

The article is sourced from here.

Researchers find novel pathway that helps eyes quickly adapt to darkness

It's almost time for the movie to start. As you hurry from the lobby into the darkened theater, you may have to stop, as the transition from light into darkness renders you temporarily blind. Cells in the eye's retina must adapt before you can begin to distinguish heads from backs of chairs. As the cells adjust, sight will be restored enough to avoid tripping over a chair, or sitting in a stranger's lap!

Scientists have long known that these cells, called photoreceptors, are involved in this adaptive process, but a study from investigators at Washington University School of Medicine in St. Louis and Boston University School of Medicine has uncovered a new pathway in the retina that allows photoreceptor cells to adapt following changes in light exposure.

The discovery could help scientists better understand human diseases that affect the retina, including age-related macular degeneration, the leading cause of blindness in people over the age of 50. That's because the process of adapting to darkness involves the same cells that are affected in macular degeneration and other blinding retinal diseases.

The findings are reported online in the journal Nature Neuroscience and will be the cover story in the March print edition.

The retina's two main light-sensing cells are the rods and cones. Both use similar mechanisms to convert light into vision, but they function differently. Rods are highly sensitive and work well in dim light, but they can quickly saturate with light and stop responding. They don't sense color either, which is why we rarely see colors in dim light.

Cones, on the other hand, allow us to see colors and can adapt quickly to stark changes in light intensity. The research team focused on cone cells, studying their ability to continue functioning in very bright light and to adapt quickly when that light is shut off.

"Rods can take up to an hour to adapt to darkness," says principal investigator Vladimir J. Kefalov, Ph.D., Assistant Professor of Ophthalmology and Visual Sciences. "Cones, by contrast, adapt in three to five minutes."

Scientists have known for years that light-sensing molecules bind together to make up visual pigments. Those pigments are destroyed when they absorb light and must be rebuilt, or recycled, for the cone cells to continue sensing light. In order to be recycled, key components of pigments called chromophores leave the retina, and travel to the eye's retinal pigment epithelium where the chromophore is restored and returned to the retina.

"If the chromophores cannot be recycled, cone cells gradually run out of visual pigment and can't detect light," Kefalov says.

But the process of traveling to and from the pigment epithelium takes too long to explain how cones quickly adapt to darkness following exposure to bright light, so Kevalov's team went looking for a second, supplementary pathway.

Working in salamander eyes, the research team removed the pigment epithelium layer so that pigment molecules could not be recycled using the known pathway. When the scientists exposed the retina to bright light and then to darkness, the cones continued to function, even without the pigment epithelium. That meant the pigment molecules were recycled in spite of the fact that they could not travel to the pigment epithelium.

"So it was clear that a second pathway is being used by the cone cells," Kefalov says.

But where? Biochemical evidence had suggested cells called Müller cells might be involved. Like glial cells in the brain that support and interact with neurons, Müller cells in the retina support and interact with photoreceptors. The researchers treated salamander retinas with a chemical that destroyed the Müller cells.

They repeated the experiment exposing the retina to bright light, followed by darkness. "And by blocking the function of Müller cells, we prevented the recycling of chromophores. The cones ran out of photopigment and could not adapt to dark," Kefalov says.

The group then conducted the same series of experiments in the mouse retina, with the same results, suggesting the second pathway involving Müller cells also is important in the mammalian eye. If it is active in the human eye, Kefalov believes it may be possible one day to manipulate this pathway to improve vision when the other one involving pigment epithelium has been interrupted by injury or disease.

One such disease is age-related macular degeneration, where cone cells begin to malfunction over time. Because the disease and the pathway Kefalov's team identified both involve cones, he says it may be possible someday to target that pathway, rev up its activity and supplement or rescue the function of cones.

Before that happens, he says it will be important to figure out exactly how the Müller cells are interacting with photoreceptors. Although these studies confirmed the existence of the second photoreceptor pathway, they didn't reveal how it works. Kefalov's laboratory has recently received a five-year, $1.9 million National Eye Institute grant to study how this newly identified visual pathway functions in the retina.

If you wish to reacd this paper, please click here.

News from the website of Washington University in St. Louis.

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.

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.