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.

Source

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.

Source

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.

Stem cells for treating Diabetic Retinopathy

An article, recently published in the PLOS, refers to pericytes derived from adipose-derived (or in lay terms, fat-derived) stem cells (ASCs), being able to integrate with retinal vasculature, and providing functional vascular protection in animal models.

(c) Robert M Hunt

Pericytes are contractile cells that wrap around endothelial cells of capillaries and venules throughout the body. These cells regulate capillary blood flow, the clearance and phagocytosis of cellular debris, and the permeability of the blood-retinal barrier. A deficiency of pericytes can cause the barrier to break down, leading to leakage of blood and other products.

Diabetic individuals often exhibit loss of pericytes in their retina. This is a characteristic sign early on in the disease. These cells are important for the protection of endothelial cells in the retina. With their loss, microaneuryms form in the capillaries, which is the earliest clinical sign of diabetic retinopathy.

ASCs have been found to differentiate into pericytes, which suggests they may be useful as protective and regenerative cellular therapy for retinal vascular disease.

The PLOS study was undertaken by Thomas A Mendel and his colleagues, a majority of whom are from University of Virginia, Charlottesville. They found that when ASCs were injected intravitreally (inside the eye) into a murine eye subjected to oxygen-induced retinopathy (OIR) (which resembles diabetic retinopathy), the cells were capable of migrating to and integrating with the retinal vasculature. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented more than 50% of retinal capillary dropout (which is commonly seen in patients with diabetic retinopathy). . Injected ASCs also prevented capillary loss in the diabetic retinopathic mouse model (79% reduction observed 2 months after injection).

The authors have concluded that ASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple animal models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with additional (TGF-β1) treatment, as seen with native retinal pericytes. 

The authors feel that ASCs may represent an innovative cellular therapy for protection against and repair of diabetic retinopathy and other retinal vascular diseases.

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

POSITIVE PRELIMINARY RESULTS FROM PHASE 1b TRIAL OF QLT091001 IN SUBJECTS WITH RETINITIS PIGMENTOSA DUE TO RPE65 AND LRAT MUTATIONS

QLT Inc. has announced positive preliminary results from its international multi-center Phase 1b proof-of-concept clinical trial of QLT091001 for the treatment of Retinitis Pigmentosa (RP) due to inherited genetic mutations in retinal pigment epithelium protein 65 (RPE65) or lecithin:retinol acyltransferase (LRAT) (also known as early-onset RP). 

The Phase 1b study showed rapid, statistically significant and clinically meaningful changes in visual fields (VF) from baseline values, as well as improvements in visual acuity (VA), in the study of 17 RP subjects. In addition, small subsets of RP subjects were investigated for secondary effects on other key vision parameters impacted by RP, such as decreased retinal sensitivity, and the data available in these subsets showed notable and promising increases in average sensitivity levels. The single-course treatment data with QLT091001 represents the first stage of dose regimen testing as the basis for a longer term multiple course regimen in RP due to mutations in RPE65 and LRAT. 

RP is a disabling group of genetic eye diseases associated with progressive loss of vision including night blindness, constricted peripheral vision resulting in difficulties with daily activities, and in later life, reduced central vision, inability to read, and in many cases progression to severe blindness. RP can be caused by many different gene defects and symptoms can start at varying ages; patients with mutations in the RPE65 and LRAT genes tend to show vision loss very early in life (this type of RP is also known as early-onset RP).

In the open-label, multi-center Phase 1b clinical study, 17 subjects (ranging in age from 6 to 55 years, mean 29 years) with either RPE65 (12 subjects) or LRAT (5 subjects) mutations received a 40 mg/m2/day dose of QLT091001 once daily for seven days with post-treatment follow-up at 7, 14, and 30 days. Visual fields and visual acuity are key measures of clinically relevant visual function. VF was assessed using Goldmann Visual Fields (GVF) and VA was assessed using best-corrected visual acuity (BCVA, ETDRS letters); GVF maps were converted to assess the remaining functional retinal area for analysis. After a single 7-day course of treatment with QLT091001, the average retinal areas from baseline showed statistically significant improvements of 34% at day 7 (p=0.005), 29% at day 14 (p=0.02) and trended towards a statistically significant improvement of 23% at day 30 (p=0.07) in the evaluable subjects meeting GVF test criteria (n=14 subset). In the intent-to-treat (ITT; all subjects enrolled) analysis (n=17), the average retinal area from baseline improved by 22% at day 7 (p=0.03, statistically significant), 16% at day 14 (p=0.13) and 18% at day 30 (p=0.096). The evaluable subset of 14 subjects excludes three patients in the VF analysis because they did not meet criteria as determined by a third-party reader. Nine of 17 subjects (53%) showed an improvement in VA over baseline in at least one eye by greater than or equal to five ETDRS letters. 

Measurement of Goldmann Visual Field Improvement from Baseline
GVF analysis – retinal area	Day 7	Day 14	Day 30
Avg. increase from baseline – evaluable subjects (n=14) Avg. increase from baseline – ITT (n=17)	34% (p=0.005)* 22% (p=0.03)*	29% (p=0.02)* 16% (p=0.13)	23% (p=0.07) 18% (p=0.096)

(*statistically significant)

Following single-course treatment with QLT091001, the Retinitis Pigmentosa patients in the clinical trial experienced a rapid and significant improvement in certain visual function parameters, as per Dr. Hendrik Scholl of the Wilmer Eye Institute at Johns Hopkins University. He also added that the discovery of the genetic cause of retinal degeneration has revolutionized insight into disease processes at a molecular level and has given the physicians encouragement for potential therapeutic approaches.  

Baseline values in subjects showed a broad range of moderately to severely reduced visual acuities and visual fields. All subjects reported early onset of night blindness as one of the hallmarks of disease.

Additional tests included spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), and quality of life assessments. Also, in small subsets of subjects, the effects of QLT091001 on several parameters of light sensitivity in dim light (night vision), pupillary reflexes, and responses of the visual cortex to potential changes in visual stimuli (functional magnetic resonance imaging, fMRI) were measured.

The fMRI substudy (n=2) showed activation of several previously quiet areas of the visual and parietal cerebral cortex after treatment. In addition, the substudy in dark adapted visual fields (n=2) showed a 16- fold average increase in sensitivity at 10%-50% of locations tested in each eye within days of the first dose. With longer dark adaptation, light sensitivity increases averaged 40-80-fold greater than baseline at 40%- 83% of the locations tested. Full-field sensitivity (FST) and pupillometry results supported the large increases in sensitivity in both eyes.

The additional secondary endpoints evaluated to date in this study support and are consistent with the changes in VF and VA observed following single course treatment with QLT091001.

Ongoing analysis of the safety profile of QLT091001 demonstrates a safety profile consistent with the Company’s Phase 1b study in patients with Leber Congenital Amaurosis (LCA). A retreatment study for the RP cohort has been initiated to assess the effects of repeat QLT091001 therapy in these patients. The database on this study remains open and further analyses of additional anatomic tests (OCT) and retinal sensitivity tests (ERG) are also ongoing to further explore the optimal baseline characteristics of responders for clinical development purposes.

The RP (early-onset RP) Phase 1b clinical study is being conducted at seven leading centers for the treatment of inherited retinal diseases in the U.S., Europe and Canada.

About Synthetic Retinoid Drugs
Genetic diseases in the eye such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) arise from gene mutations of enzymes or proteins required in the biochemistry of vision. QLT091001 is a replacement for 11-cis-retinal, which is an essential component of the retinoid-rhodopsin cycle and visual function, and is under investigation for the treatment of LCA and RP. QLT091001 has received orphan drug designations for the treatment of LCA and RP by the European Medicines Agency, and for the treatment of LCA and RP due to inherited mutations in the LRAT and RPE65 genes by the U.S. Food and Drug Administration (FDA). The drug has also been granted two Fast Track designations by the FDA for the treatment of the LRAT and RPE65 genetic mutations in both LCA and RP.

About Leber Congenital Amaurosis (LCA)
LCA is an inherited degenerative retinal disease characterized by abnormalities such as roving eye movements and sensitivity to light, and manifesting in severe vision loss from birth. Both rod and cone photoreceptors are affected in LCA. Eye examinations of infants with LCA reveal normal appearing retinas. However, a low level of retinal activity, measured by electroretinography, indicates very little visual function. According to current epidemiological estimates, LCA affects approximately one in 81,000 newborns worldwide, of which approximately 10% carry the inherited deficiencies of either RPE65 or LRAT.

About Retinitis Pigmentosa (RP) Due to RPE65 and LRAT Mutations
RP is a set of hereditary retinal diseases demonstrating clinical features similar to LCA. RP is also characterized by degeneration of rod and cone photoreceptors, but it presents with a more variable loss of vision in late childhood to adulthood. Deficits in dark adaptation and peripheral vision are particular hallmarks of RP. RP is currently estimated to affect at least 300,000 individuals worldwide, of which approximately 20%–30% are autosomal recessive (arRP). It is currently estimated that less than 3% of autosomal recessive RP patients carry the inherited deficiencies of either RPE65 or LRAT.

About QLT
QLT is a biotechnology company dedicated to the development and commercialization of innovative ocular products that address the unmet medical needs of patients and clinicians worldwide. We are focused on developing our synthetic retinoid program for the treatment of certain inherited retinal diseases, developing our proprietary punctal plug delivery system, as well as U.S. marketing of the commercial product Visudyne® for the treatment of wet age-related macular degeneration.

Derived from the press release from QLT Inc.

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 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.

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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.

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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."

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