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. 

Of disclosing ‘disability’ before marriage

There was a time when my mother and sister were searching a bride for me. I had insisted to have my visual ‘disability’ (as others call it) be totally disclosed. People initially showed interest and willingness in my proposal, but the moment my Retinitis Pigmentosa-caused blindness was disclosed, either they did not carry the issue further or politely tendered their refusals.

My parents and sister used to feel sorry for this, and they found it difficult to tell me that I again am being refused for the fear that I will get disheartened. But I had not committed a guilty or shameful act due to which I was facing rejections, so I saw no reason to get disheartened. Indeed, the fact that people were interested in me until my blindness was disclosed was a positive point for me. I have not caused my blindness; it is caused due to reasons beyond my control, then why to feel sorry over it? Yet, I must confess that sometimes I used to feel dejected, but there was light at the end of the tunnel.

We had a very old friendship with a family. They used to frequent us often, and once all of a sudden my mother kept my marriage proposal to them. They gladly agreed, the mother of my supposed wife merrily telling us “What is the use of asking? My daughter is yours, we know your son, he is our child, everything is settled.”

Both the families came in the mood to have a great celebration. Marriage celebrations or their preparations seem to be so divine that we feel as if everyone, even our bloodthirsty enemies, are loving and blessing us in their hearts. The noteworthy thing was that we had visited each other so much that it was clear that they know about my blindness. Moreover, my sister too has RP, and they had helped her often. Yet my sight problem was impressed upon them. But they just did not listen to us and even told my sister not to talk about that issue again as if it was hurting them.

Marriage is a big thing. Everything was clear but I felt some uneasiness and requested to talk with the girl because I did not want to take chances.

We went to meet them. It turned out that they were not taking my sight problem seriously because they were thinking that I have enough sight to do my work on my own. For instance, they knew that I work on computers and move around the city and out of the city independently (at the time these talks were taking place I was out of station). But the astonishing thing was that they could not realise that in the course of time I have become blind.

I told her mother point-blank: “I can only see light. I am looking towards your face because of your voice. I use screen reading technology to work on computers. And I use a cane when I walk alone. I cannot see.”

She gave a pause. That pause clearly expressed that she was broken. (Later, I came to know from my mother that her hands were shaking at that time.) Then I talked with the girl who had already known about the new condition I was in. She sounded perplexed and disinclined.

Their reaction, though, was normal. Anyone would have reacted in a similar manner after knowing about my blindness. My marriage date was to be fixed, but now they needed time and told us that they were unaware that I had lost my sight. I thought that the game was over.

But I was wrong.

Days passed. One good evening, the mother of the girl-who-could-be-my-wife came to our home and started showering praises on me. She talked to me in a tearfully sympathetic tone, though I had not needed it. Apologising from her expressions and tone, she told us that her daughter was not willing to marry me. I was thankful because if this condition had disclosed after marriage, I would have been in great trouble.

At my home, I gave a small party to my friends, and called it ‘In the name of my cancelled marriage’! It was meant to truly celebrate life; it was not one of those Bollywood parties in which bottles are uncorked, there is false enjoyment all around, and the main character ineptly tries to forget his grief in the make-believe. Thankfully, we really enjoyed our party, and since my room is quite separated, we made a lot of noise until the early hours of the morning.

Days passed. Wham! The mother of   the girl-who-could-be-my-wife told us that her daughter wants to marry me! She was deeply moved by that honesty stuff. Earlier too, that delicate creature had cried and prayed for me a lot, on hearing that I have become blind. Her family members, too, had prayed and cried, and now the girl was willing to marry me. It was a U-turn!

Can you even guess what happened after that? Celebrations, excitement, religious and cultural rituals... no, nothing of the sort.

I was not very impressed with prayers and tears. (Though I always beg for God’s mercy and crave for prayers of His creations.) I had earlier told my sister that they have the right to reject me, but acceptance after rejection will not affect me.

I remained a bachelor.

I started to train myself to lead an unmarried life. I found many people (including two blind men) who were very sufficiently leading a lonesome life and asked myself: “If they can do it, why cannot I?”

Living alone is difficult, but not impossible. Loneliness humbles you, brings forth your good qualities and teaches you how to be happy in need. It is a lovely teacher which urges you to be independent of all except God.

I was not pessimistic to adopt such an approach; I only tried to be practical. Had I been pessimistic, I would have told my family members not to search a bride for me because “I want to live alone.” Besides, I have a small rule of life, which is to try to be happy in an unnatural or adverse situation, but never to willingly prolong or embrace it. True, bearing pain patiently brings forth our good qualities, but this does not mean that we don’t take steps to eliminate it.

I lived and enjoyed the present without caring about the future. I pursued my hobbies (reading, writing and travelling) and tried not to miss a chance to improve myself.

Days passed. The final shot readers! One fine evening I was introduced to a girl by my mother and sister to whom I told each and everything about my sight. It is close to midnight now, and guess what....that girl is with me because thankfully she is my wife!

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Shadab Husain works as a receptionist at Chhatrapati Shahuji Maharaj Medical University, Lucknow. He has an MA in English literature, and has pursued a diploma in computer applications as well as a personality development course. He also writes a blog on personality development and improving English. To visit his blog, click PersonalityAndEnglish.blogspot.com.

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

First human induced Pluripotent Sem cell therapy eyed in 2013

A clinical study into the use of lab-grown retina cells to treat age-related macular degeneration (AMD) has been slated for fiscal 2013, a senior staffer of the research body planning to undertake the project said Saturday.

The project might be the world's first to use induced pluripotent stem cells, or iPS cells, for the treatment of human diseases. 

The study will initially target several patients with the eye disease whose vision cannot be sufficiently restored through existing medication. It will then be expanded to include earlier-stage patients once the safety of the iPS cell treatment can be determined.

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Scientists find an answer to one of still unsolved mysteries of the eye

Scientists have a good overall understanding of human vision: when light enters our eyes, it is focused by the lens and strikes the retina in the back of the eye. The light causes some of the millions of photoreceptor cells that line the retina to undergo a chemical change, which send a message through the optic nerve to the brain, which ultimately creates an image. However, there are still a few unresolved questions in the details of the vision process, one of which is why the eye evolved to use a certain light-absorbing chromophore called 11-cis-retinal, instead of one of its isomers (i.e., molecules with the same atoms but in different arrangements), such as 7-cis, 9-cis, or 13-cis.

Chemists Sivakumar Sekharan from Emory University in Atlanta, Georgia, and Keiji Morokuma from Emory University and Kyoto University in Kyoto, Japan, describe the eye’s use of 11-cis-retinal as “one of the basic and unresolved puzzles in the chemistry of vision.” But by taking advantage of the rapid advances in hybrid quantum mechanics/molecular mechanics (QM/MM) computational modeling, the researchers have found that the answer to this puzzle lies in electrostatic interactions in the retina. Their study is published in a recent issue of the Journal of the American Chemical Society.

The retina contains light-sensitive photoreceptor cells known as rods and cones, which convert incoming light into electrical impulses that are sent to the brain. On the top of every rod and cone is a region that contains opsin proteins bound to 11-cis-retinal chromophores, which together are called rhodopsin. When light strikes the retina, the 11-cis-retinal chromophores absorb the light, which causes them to undergo an isomerization and change their molecular configuration from 11-cis-retinal to all-trans-retinal in a matter of picoseconds. The difference between these two isomers involves the positions of the hydrogen atoms, a shape change that causes the opsin protein to change shape in response. The opsin shape change, in turn, leads to a cascade of biochemical reactions in the photoreceptor cell that ultimately generate an electrical impulse.

Since the 11-cis-retinal is the retina’s first responder to incoming light, its unique geometric configuration clearly plays an important role in the vision process. However, theoretically there are a handful of other retinal isomers that seem capable of performing this task, yet for some reason photoreceptor cells only function with 11-cis-retinal (and the corresponding 11-cis-rhodopsin).

“Because the primary event in vision involves no breaking of chemical bonds but only a conformational change in the shape of the molecule from bent cis to the distorted all-trans form, scientists wondered why 7-cis-, 9-cis- or 13-cis- isomers could not achieve this goal,” Sekharan told PhysOrg.com.

To answer this question, the researchers built computational models of the rhodopsin found in the eyes of cows, monkeys, and squids. While all known animals’ eyes use 11-cis-retinal, the opsin in different animals contains different numbers and positions of amino acids. Using a cutting-edge QM/MM modeling method called ONIOM (Our own N-layered Integrated Molecular Orbital), the researchers prepared models that matched different animals’ opsins with 7-cis, 9-cis, 11-cis, and 13-cis molecules serving as chromophores. In these artificial rhodopsins, the researchers analyzed the structure, stability, energetics, and spectroscopy to try to find out what makes 11-cis-retinal nature’s preferred isomer.

The results of the modeling showed that differences in the electrostatic interactions between the opsin protein and the retinal chromophore played the biggest factor in the natural selection of 11-cis-retinal over the other cis isomers. Due to electric charges, the link between 11-cis-retinal and opsin has a higher stability than the links between other cis isomers and opsin, making it the most favorable choice.

“Our results show that the strong electrostatic interaction between retinal and opsin favors the natural selection of 11-cis- over other cis-isomers and arguably prepares the chromophore for the upcoming photochemical event,” Sekharan said. “This indeed is very surprising given the fact that, outside the protein environment, 11-cis-retinal is one of the least stable isomers. Apparently, our results on cow, monkey and squid demonstrate that organisms everywhere may tend to gravitate towards common selection.”

Sekharan added that the results not only provide a better understanding of the eyes on a molecular level, but could also have applications for artificial retinas.

“Because rhodopsin serves as a decisive crossing point between an organism and its environment, we have been always impressed with this interesting interface by seeing it, say, from the outside and not from the inside,” he said. “Using the ONIOM-QM/MM method we developed, we can ‘enter’ deep into the dark side of this fascinating molecule. One of interesting findings to emerge out of our investigation is that 9-cis-retinal is only slightly higher in energy compared to 11-cis-retinal. This provides strong evidence for the presence of 9-cis-rhodopsin in nature, which in turn may well aid in optimizing the parameters required for designing artificial retinas.”

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.

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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."

Source & Source

FDA grants orphan drug status for Santen Inc.'s Sirolimus (DE-109)

Santen Inc., the U.S. subsidiary of global ophthalmic pharmaceutical company Santen Pharmaceutical Co., Ltd. (Osaka, Japan), & Global Clinical Development and Medical Affairs at Santen today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for sirolimus (DE-109) for the treatment of chronic/refractory anterior non-infectious uveitis, non-infectious intermediate uveitis, non-infectious panuveitis, and non-infectious uveitis affecting the posterior segment of the eye. The designation follows the granting of orphan drug status by the European Commission in September 2011.

About Sirolimus: 
Sirolimus was isolated in the 1970’s from Streptomyces hygroscopicus in soil samples from  Easter Island. Sirolimus is the active pharmaceutical ingredient in two products approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), specifically, Rapamune®, an immunosuppressive agent used in renal transplant patients, and the CYPHER® Sirolimus-eluting Coronary Stent approved for improving coronary luminal diameter in patients with symptomatic ischemic disease.

Sirolimus, originally known as rapamycin, is a broad-acting compound that is known to be an immunosuppressive and anti-proliferative agent. It is currently being evaluated in a Phase III study entitled SAKURA (Study Assessing double-masKed Uveitis tReAtment), to assess the safety and efficacy of different doses of sirolimus in non-infectious posterior uveitis. (If you are an expert and want to know the clinical trial details, please click here.)

About Uveitis:
Uveitis is a group of intraocular inflammatory disorders with both infectious and autoimmune  etiologies. Typically uveitis is classified by anatomic location in the uvea. Anterior uveitis is the most common type and can involve the cornea, iris, and/or ciliary body. Intermediate uveitis affects the middle portion of the eye, such as the ciliary body and vitreous. Posterior uveitis can involve the vitreous, choroid, retina, and/or optic nerve. Panuveitis, also referred to as diffuse, can encompass anterior, intermediate, and posterior segments. 

Sound of football (or soccer ball) allows visually challenged players to play the game

In a show of just how far smartphone technology has come, a new group funded by the Pepsi Refresh Project, has put together various technologies that allow blind people to play football (or soccer) using nothing but sounds that come to them from headphones connected to an iPhone mounted on their helmet. The idea, developed by Akestam Holst and Society 46, is to use surround sound technology to allow someone who cannot see, to move around and interact in an unknown and constantly changing real world environment. To demonstrate their technology, they set up a match between a group of sighted, but blindfolded former pro footballers, and a group of blind players on a small portion of a real stadium.

To create the sounds that guide the players, the team used 3D camera systems provided by Tracab mounted on the stadium walls. The cameras are connected to computers with tracking software that allows for the tracking of each player, the ball and the location of the goal posts. Each tracked entity is assigned a unique sound which is modified based on its relative location to each player then broadcast to the iPhone on the player’s helmet. Thus, when a player on the field approaches another, the sound that is generated not only gets louder, but is “projected” in three-dimensional space, which means the player can tell where the other player is relative to them, just as people can tell where someone is relative to them who is walking on a tiled floor with hard soled shoes, by the direction of the sound waves coming at them. Because of this effect, the sound can be adjusted in real time when the player listening moves on the field. And because of the gyroscope and the compass in their iPhone, the effect can be adjusted as the player turns their head, providing a continuous perspective.

In short, the whole system allows each individual player to “hear” where everyone else is, where the ball is, where on the field they are, and where the goal posts are. Based on that information, each player can then move about as they would were they able to do so using vision. Granted, the system can’t possibly offer anywhere near the same sensory experience as those who can see, but it is enough to allow the teams to both play and compete.

In the end, each side had its own advantages. The ex pros obviously had far superior ball skills, while the blind players had far more experience moving around the real world without benefit of sight. And it appears things worked out rather evenly, as the final score was 1-1.

To read more about it, click here, here, here and here. If you want to watch the videos of the technology or the actual game, please click here and here.

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Diabetes can lead to memory loss, depression and other cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked.

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease.

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events.

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent."

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes.

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls.

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow.

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines.

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. "

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity.

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes.

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed."

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Does space flight impact astronauts' eyes and vision?

A new study sponsored by NASA finds that space flights lasting six months or more can cause a spectrum of changes in astronauts' visual systems. Some problems, including blurry vision, appear to persist long after astronauts' return to Earth. The results are affecting plans for long-duration manned space voyages, such as a trip to Mars.

The study team included ophthalmologists Thomas H. Mader, MD, of Alaska Native Medical Center and Andrew G. Lee, MD, of The Methodist Hospital, Houston, Texas. Their report is published in October's Ophthalmology, the journal of the American Academy of Ophthalmology.

The researchers studied seven astronauts, all of whom were about age 50 and had spent at least six continuous months in space. All reported that their vision became blurry, to varying degrees, while on the space station. Vision changes usually began around six weeks into the mission and persisted in some astronauts for months after their return to Earth. Drs. Mader and Lee agree that the eye abnormalities appear to be unrelated to launch or re-entry, since they occurred only in astronauts who spent extended time in microgravity.

In-depth examination of the seven astronauts revealed several abnormalities. All of the subjects had one or more of the following changes in the tissues, fluids, nerves and other structures in the back of the eye:

• Flattening of the back of the eyeball (five subjects);
• Folds in the choroid, the vascular tissue behind the retina, which is the light sensitive area in the back of the eye (five subjects); and
• Excess fluid around and presumed swelling of the optic nerve (five subjects).

Such abnormalities could potentially be caused by increased intracranial pressure−that is, pressure inside the head. However, none of these astronauts experienced symptoms usually associated with intracranial pressure, such as chronic headache, double vision, or ringing in the ears. Researchers believe other factors may be involved, such as abnormal flow of spinal fluid around the optic nerve, changes in blood flow in the choroid, or changes related to chronic low pressure within the eye, which is known as intraocular pressure. They hypothesize that these changes may result from the fluid shifts toward the head that occur when astronauts spend extended time in microgravity.

The visual system changes discovered by the researchers may represent a set of adaptations to microgravity. The degree and type of response appear to vary among astronauts. Researchers hope to discover whether some astronauts are less affected by microgravity and therefore better-suited for extended space flight, such as a three-year round trip to Mars.

In their report, Drs. Mader and Lee also noted a recent NASA survey of 300 astronauts that found that correctible problems with both near and distance vision were reported by about 23 percent of astronauts on brief missions and by 48 percent of those on extended missions. The survey confirmed that for some astronauts, these vision changes continue for months or years after return to Earth. The possibility of near vision problems has been recognized for decades, and special "space anticipation glasses" to improve visual sharpness have been provided on all spacecraft dating back to John Glenn, who had a pair in his space capsule.

"In astronauts over age 40, like non-astronauts of the same age, the eye's lens may have lost some of its ability to change focus," said Dr. Mader. "In the space program's early days most astronauts were younger, military test-pilots who had excellent vision. Today's astronauts tend to be in their 40s or older. This may be one reason we've seen an uptick in vision problems. Also, we suspect many of the younger astronauts were more likely to 'tough out' any problems they experienced, rather than reporting them."

As part of ongoing research all astronauts now receive comprehensive eye exams and vision testing. Diagnostic tests include pre- and post-flight magnetic resonance imaging, optical coherence tomography, which magnifies cross-section views of parts of the eye, and fundus photography, which records images of the retina and back of the eye. Intraocular pressure measurement and ultrasound imaging take place in flight, as well as pre- and post-mission.

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Is pupillary light reflex really controlled by the brain?

You’ve seen it on television: A doctor shines a bright light into an unconscious patient’s eye to check for brain death. If the pupil constricts, the brain is OK, because in mammals, the brain controls the pupil. Or does it? Now, researchers at Johns Hopkins have discovered that in most mammals, in fact in most vertebrates, the pupil can constrict without any input from the brain. Their work, which also describes for the first time the molecular mechanism underlying this process, appears in the Nov. 3 issue of Nature.

“It was established more than 40 years ago that animals like amphibians and fish have photosensitive irises and don’t necessarily require the brain for the pupillary light reflex, whereas it was thought that mammals generally required brain circuitry,” says King-Wai Yau, Ph.D., professor of neuroscience and ophthalmology at the Johns Hopkins University School of Medicine and member of the Institute for Basic Biomedical Sciences Center for Sensory Biology. “But in neither case did anyone know what the molecular switch was, and now we have found that it’s the pigment melanopsin.”

The research team examined isolated irises from a wide range of mammals by attaching a tiny meter that measures the force of the sphincter muscle that constricts the pupil. They then shined a bright light onto this muscle and measured any contraction. Irises from nocturnal animals including mouse, rat, hamster, dog, cat, rabbit and the Nile grass rat all showed responses to light. Irises from diurnal animals including guinea pig, ground squirrel and pig did not, nor did those from rhesus monkey, marmoset, owl monkey and bush baby, even though the owl monkey and bush baby are nocturnal.

“Most non-primate mammals are considered nocturnal or crepuscular — active at dawn and dusk — including those, like dogs, that have been domesticated and have picked up human circadian rhythms,” says Yau. “We don’t really know why primates, including us, as well as other daytime functioning animals don’t have this ability.” According to Yau, the eyes of nocturnal animals, because they function in the dark, contain more cells that are sensitive to low light and exposure to bright light could cause eye damage. Perhaps, he suggests, the built-in pupil reflex is a good way to protect the eye.

“So we wanted to know what pigment molecules are involved in triggering pupil constriction,” says Yau. Having previously genetically engineered mice to lack melanopsin, the team first tested the pupillary light reflex on irises from these mice. “That was a really exciting result—they didn’t respond to the light,” says Tian Xue, a research associate with Yau. They also tested mice engineered to lack other light-capturing pigments, but all of them responded normally, suggesting that only melanopsin is required for the local pupil reflex. Using mouse genetics, the team then continued to try to identify other proteins that work with melanopsin to cause the pupil to contract in response to light.

Because melanopsin is closely related to the pigment responsible for capturing light in fly eyes, and that molecular pathway has been well studied, Yau’s team hypothesized that the mammalian counterparts to these fly molecules might be what works with melanopsin. So they tested mice engineered to lack some of these molecules. They found that irises from mice lacking the PLC enzyme were unresponsive to light, showing that PLC also is involved in this reflex.

There still are a lot of things we don’t know that we would like to study,” says Yau. “Now that we know what captures the light and starts the local reflex, we would like to know what proteins in the muscle trigger the actual contraction.”

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Nature's Editorial Summary: "Mammalian pupil sees the light"

Contraction of the mammalian iris in response to light has been thought to require neuronal circuitry connecting the retina to the brain. Now King Yau and colleagues report the surprising observation that in a wide variety of mammals, the eye's pupil is intrinsically photosensitive. Iris muscles isolated from nocturnal mammals such as mice — but not from primates — contract when exposed to light through the action of a melanopsin-based signalling pathway that partially overlaps with its retinal counterpart. Previously, the intrinsic pupillary reflex was thought to be an exclusive property of lower vertebrates such as fish, amphibians and birds. For those who want to read the article in detail, please click here.

First patient receives novel gene therapy for a type of blindness

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Possible new treatment for Complicated Retinal Detachments with Proliferative Vitreo-Retinopathy (PVR)

Proliferative vitreoretinopathy (PVR), or the formation of scar tissue within the eye, is a serious, sight-threatening complication in patients recovering surgical repair of retinal detachment. A new study conducted by investigators at the Schepens Eye Research Institute, the Department of Ophthalmology at Harvard Medical School, and the Massachusetts Eye and Ear Infirmary in Boston, USA, published in the December issue of the American Journal of Pathology, suggests that a cocktail containing reagents to neutralize a relatively small subset of vitreal growth factors and cytokines may be an effective treatment.

The investigators, lead by Andrius Kazlauskas, PhD, of The Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, found that a combination of 7 classes of growth factors and cytokines was essential for PVR to develop in animal models of the disease. By neutralizing them, they were able to prevent PVR-relevant signaling, and inhibit contraction of collagen gels containing primary retinal pigment epithelial cells derived from a human PVR membrane (RPEMs). These findings suggest a potential therapeutic approach to reduce the incidence of PVR in patients undergoing surgery to repair a detached retina.

In animal models, platelet-derived growth factor receptor α (PDGFRα) is associated with PVR and strongly promotes experimental PVR. Vitreal growth factors outside of the PDGF family promote an indirect route to activate PDGFRα. Importantly, indirectly activated PDGFRα engages a characteristic set of signaling events and cellular responses that are tightly associated with PVR. This study sought to identify the factors that would induce those events, and develop therapeutic approaches to prevent patients from developing PVR.

Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous was found to contain substantial levels of growth factors and cytokines, which change quantitatively or qualitatively as PVR develops. A set of nine growth agents was found to be most abundant and therefore most likely to contribute to PVR. Neutralizing a subset of these factors in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single dose of neutralizing reagents effectively protected rabbits from developing retinal detachment.

To identify growth factors likely to be driving PVR in humans, the investigators quantified the level of growth factors and cytokines from human donors that had either PVR, or a non-PVR retinal condition. Fourteen of the 24 agents quantified were present in large concentrations in PVR vitreous. Neutralizing just 7 of these prevented vitreous-induced activation of PDGFRα. Furthermore, the cocktail also suppressed the contraction of these cells in collagen. Therefore, the same neutralization strategy that prevented PVR in rabbits also prevented human PVR vitreous from inducing PVR-relevant responses. These results strongly suggest that a dose of neutralizing reagents may also protect humans from PVR.

Although it sounds encouraging, the investigators feel they need to test the effectiveness of this treatment on alternate models of retinal detachment. They are considering a combinatorial approach to therapy. For example, the antioxidant N-acetylcysteine (NAC) is known to prevent retinal detachment in rabbits by blocking intracellular processes. A combined therapy involving the neutralization approach by these investigators, along with NAC treatment, would target PVR at both the extracellular and intracellular levels, thus possibly helping in treatment.

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