State and National News

THEACHIEVER Retina Australia Victoria Registration # A0002991W SUMMER EDITION DECEMBER 2010

ROSS HOUSE, 4TH FLOOR 247 - 251 FLINDERS LANE MELBOURNE VIC 3000 PHONE (03)9650 5088 FAX (03) 9639 0979 Email: [email protected] INSIDE Web site: www.retinavic.org.au

FROM THE PRESIDENT 2 RETINA AUS MEDIA RELEASE 4 SIZZLING FEATURE: STEM CELL TREATMENT PUTS 5 POLICE DOG BACK ON BEAT RESEARCH UPDATE: MYSTERY OF CONE DEATH IN RP 6 INVESTIGATING REGENERATIVE 9 POTENTIAL OF RETINAL CELLS EFFICACY OF SUSTAINED TOPICAL SUMMER DORZOLAMIDE THERAPY 10 ITALIAN STUDY FOR RP 11 ADVANCEMENT IN GENE THERAPY 12 FOR DOMINANT RP NEWS RESULTS FROM FENRETINIDE 13 TRIAL FOR AMD PATIENTS STEM CELL TREATMENT FOR 14  Bumper Research Issue STARGARDT’S MD PATIENTS WHAT IS OPTOGENICS? 15  State and National News UNDERSTANDING STEM CELL 16 THERAPY – PART TWO QUESTION TIME 17 LAST WORD 17

Seasons Greetings and every good wish

for the New Year

PP: 33 1088/00015 From the President - Leighton Boyd

It is my great pleasure, on behalf of the Board of Retina Australia Victoria, to report that once again the organisation has had a financially successful year, being supported by our members, friends, donors and a small, but very dedicated group of volunteers. It is pleasing to report that our membership has continued to grow during the previous twelve months and that more members are paying their annual membership subscription by the due date. There are some subscriptions which are still outstanding and I would urge you to pay these as soon as practicable because this income provides the funds for the administration of the affairs of Retina Australia Vic. A sincere thank you to members who have included a donation along with their membership subscription, this is greatly appreciated. Increasing also, is the number of members who have chosen to receive information electronically as this assists our organisation by reducing postage and printing costs. During our Annual General Meeting held on Saturday 9 October 2010 we circulated, and spoke about, the Annual Report of the association which sets out our achievements for the previous financial year as well as our audited financial statements. If you would like a copy of this Annual Report, please contact Lin in the office on 03 9650 5088. As indicated in the financial reports, we have received a significant amount of money from donations. Many of our donors are not members but they provide donations towards retinal research. I would like to thank them most sincerely for their continued support, because monies raised from all donations has

RATHEACHIEVERP a g e 2 RETINA AUSTRALIA (VIC) INC. enabled us to continue to assist individual Australian researchers, as well as contribute to the Australian Inherited Retinal Disease Register and DNA Bank. At our AGM, we also elected the Board for the forthcoming twelve months. I would like to thank the outgoing Board members and all of our volunteers for their support and contributions during the previous year. In particular I would like to thank Rick Clarke, Graham Owen, Rosemary Boyd, Chris Edwards, Justin Marshall and Barbara Family for their preparedness to continue as Board members, and to welcome Mary Anne Carmody back to the Board after a long period of absence. Mary Anne, a former Secretary of the association, is a lawyer and thus brings an added dimension to the Board. We were extremely fortunate to have as guest speakers, at the conclusion of the AGM, Professor Michael Kalloniatis, Dr Una Grefereth and Dr Erica Fletcher who spoke to the assembled group about their personal research as well as interesting research results being achieved globally. Attendees were given the opportunity to ask questions of each speaker at the conclusion of the collective presentations. All three speakers have been recipients of research funding from Retina Australia which derives its research pool of money from the state groups. Recently, on the basis of monies raised by state groups through raffles, luncheons, dinners and other fundraising events, as well as through the sale of merchandise, Retina Australia has announced that they will be able to fund the research of three teams in 2011. The successful recipients, their project titles and the amount of support being provided by Retina Australia is listed below and we look forward to hearing about the outcomes of this research at a future AGM or the next Retina Australia Congress which will be held in Sydney in October 2012. Research Researchers and location Research Project Title Funds Allocated Drs Jamieson & Grigg Investigation for novel Eye Genetics Research Group disease genes in cone and $39,700 Children's Hospital rod dystrophies Westmead Sydney NSW Does the level of systemic Professor Guymer and Dr Lim inflammation influence the Centre for Eye Research Australia outcome of treatment in $30,000 Melbourne VIC Neovascular Age-related Macular Degeneration? Role of a novel miNRA in the Professors Hunt & Collin dominant syndromic University of WA disorder of macular $30,000 School of Animal Biology dystrophy and a split hand Perth WA and foot malformation

RATHEACHIEVERP a g e 3 RETINA AUSTRALIA (VIC) INC. During the previous twelve months there have been significant breakthroughs in research related to inherited retinal diseases throughout the world. From all reports the future is very promising with human clinical trials forecast to commence for many of the proposed treatments for inherited retinal disease during the next two years. I was closely involved with the launch of the Australian Bionic Eye project, in March, which was extremely exciting because this proposed device is leading the world in terms of the technology involved and its potential for enabling people who have lost their vision, to see again. As well, many of our members responded to the request from the Centre for Eye Research Australia (CERA) to participate in a clinical study to examine how the structure of the retina changes in patients with RP in order to develop a better bionic eye implant. Thank you to everyone who volunteered, CERA were overwhelmed, and extremely grateful, for the response. In conclusion, I would like to wish all members the compliments of the season. I hope that you all have a wonderful Christmas and a happy New Year and are able to take the time to celebrate this special time with family and friends. The Office will be closed from 2.30pm on Thursday 23 December and reopen at 9.00am on Tuesday 18 January. If you need assistance during this closure period, please do not hesitate to phone me on 0417 566 899. RETINA AUSTRALIA MEDIA RELEASE BLINDNESS PREVENTION CHIEF APPEALS FOR GOVERNMENT HELP

Graeme Banks, president of Retina Australia, has appealed to Australia’s political leaders for assistance in establishing and developing patient registers. He says that without such registers potential treatments and cures for the estimated eight thousand Australians suffering inherited retinal diseases cannot be further developed. He says his organisation has already instigated an Inherited Retinal Disease Register and DNA bank in Western Australia aimed at having all people with an inherited retinal disease and their selected blood relatives provide a DNA sample so as to assist in the search for rogue genes.

“This has been set up through the hard work of Retina Australia’s state organisations in raising the funds necessary for the project,” he says. “However, ongoing support from government and philanthropic sources is still needed to cover the significant cost of fully developing the register so as to be able to 'sequence’ the DNA samples for treatment purposes when gene therapies are available.”

“ With more projects reaching human clinical trial stage, patient involvement is more crucial than ever to the development of potential therapies. Further, we need patients, their families and other supporters to play their part in making sure successfully developed treatments are widely accessible to affected people.”

Research is intensifying throughout the world in an effort to halt the progress of retinal dystrophies and find a treatment or cure. Mr Banks says that with leading researchers RATHEACHIEVERP a g e 4 RETINA AUSTRALIA (VIC) INC. and clinicians at the helm of a number of successful vision and ophthalmology research projects, Retina Australia is confident that a cure or therapy for these conditions is within reach. In recent years more than 100 mutant genes have been identified as responsible for inherited degenerative loss of vision. Clinical trials have been conducted recently using drugs that inhibit the death of cells in the eye.

“ Clinical trials face major financial and legislative difficulties,” Graeme Banks says. “We appeal to the government to become involved in the process, from proper genetic diagnosis and genotyping through to the establishment of registries. The journey travelled by the international retinal research community to reach these exciting times has been a very long one. It is now time for patients, research funding authorities, health administrators and politicians to play their part in ensuring we reach our destination.”

“ Only by playing our part will we offset the huge emotional, social and economic effects of sight loss and blindness from diseases such as Macular Degeneration, Retinitis Pigmentosa, Usher's syndrome, Stargardt disease and others too numerous to mention.”

This is an edited version of the media release by Robin Poke – President of Retina Australia (ACT).

Stem Cell Treatment Puts Police Dog Back on the Beat

It’s hard to believe that Dasty, a 5-year-old German shepherd and member of the Chicago Police Department's narcotics unit, had been virtually crippled by severe arthritis in his left rear leg due to Lyme disease. "His quality of life was not good," says Dr. Cheryl Adams, a veterinarian at Arboretum View Animal Hospital. "The poor guy could barely stand up." Now he's as good as new, thanks to stem cell treatment, a relatively new procedure in which Dasty's own fat cells provided the stem cells that were injected into the leg. It got him up and running again. And mobility is a prerequisite for Dasty's job. He's a member of the Chicago Police Department's narcotics unit.

Initially, he received physical therapy, antibiotics and steroids, but the benefits were minor, and the side effects were not insignificant. His weight ballooned, and he developed bad eating habits. It was thought that he may have to be retired.

The stem cell treatment was developed by Vet-Stem, a Californian, company that was founded in 2002 and in 2005 began working with several clinics in treating dogs with osteoarthritis and soft-tissue injuries. About 700 dogs have received the treatment. In the procedure, a small incision is made in the abdomen, where fat cells are readily available, and some cells are removed. Fat cells are used because 1 in 50 of them is a stem cell, the highest concentration in the body. The fat cells are shipped to Vet- Stem and processed. The stem cell samples are returned and administered.

RATHEACHIEVERP a g e 5 RETINA AUSTRALIA (VIC) INC. In Dasty's case, it was both intravenously and through injection. That entire process takes just two days. The cost varies between $2,300 and $4,500, depending on the size of the dog and the number of injections needed. But the benefits are obvious.

Marion Anderson, Chicago Police veteran and Dasty’s partner of 4 years said, "It's such a heart-warming story. We were able to help out one of our service dogs when he does so much for the city. Right after one of his treatments, we were searching a cargo van, and he found $40,000," she says. "He's also found 21 kilos of cocaine, and a few months ago he found $173,000 in one search. He's a tremendous worker."

Source: Chicago Tribune, 17 September 2010

Editor’s comment:

I wonder what implications this story could have for our guide dogs, companion dogs or any of our other working dogs in Australia?

Research conducted at Harvard Medical School has provided a fresh perspective on why healthy cells die in patients with retinitis pigmentosa (RP). This long-standing puzzle may now be resolved through an improved understanding of how cones receive nutrition within the retina. A comprehensive series of experiments have shown that disturbance of an insulin-associated pathway in cone photoreceptor cells can lead to their un-timely death. The finding is of major significance due to the potential to target this pathway and thereby devise a treatment strategy that could benefit an estimated 1.5 million people who lose their sight annually from RP.

While RP is a disorder arising mainly from genetic mutations within rod photoreceptors it has been widely observed that rod cell death is invariably followed by cone cell death. For decades however, researchers have wondered why? In nearly all cases the cones are completely healthy and it is their loss, rather than the loss of rods, that causes most of the devastation in patients with RP. As cones are responsible for our fine and colour vision their degeneration inevitably leads to a significant alteration in the quality of life. Life without cones means the simple pleasures of reading, watching a movie or having the independence to drive from A to B may no longer be available.

RATHEACHIEVERP a g e 6 RETINA AUSTRALIA (VIC) INC. Further compounding the mystery of healthy cone cell death has been the equally puzzling observation that the reverse situation does not apply the same rule. In other words when one looks at disorders arising primarily from mutations in cone specific genes, cone cell death does not appear to be followed by wide spread rod cell death. Intrigued by these observations Drs. Claudio Punzo, Karl Kornacker and Constance Cepko of the Harvard Medical School in Massachusetts, conducted a series of experiments to explore how this apparent riddle might be resolved. While modern life and technology provides the capacity to avoid dim lighting conditions the loss of rod photoreceptor cells may not appear as a major devastation. However, the inevitable loss of the cone cells following rod cell death is where the true impact of the disease is realised. The research team at Harvard led by Dr. Cepko wanted to understand what was causing this cone cell death and, by finding the cause, potentially explore if any therapeutic intervention might be possible to extend the life span of cone photoreceptor cells.

The researchers examined four mouse models of RP used in several research labs around the world. In each instance, as had been previously reported, a mutation in a rod specific gene leads to the death of rod photoreceptors. In each of the models cone cell death always started at the end of the rod cell death phase and additionally appeared to spread from the central retina to the periphery. Although the timing of the phases was different in the different models there were sufficient common features to suggest that an under-lying common mechanism might explain the kinetics of cell death. To see if such a common mechanism could be found the research team decided to analyze global gene expression in the rod and cone photoreceptors. Using sophisticated gene chip technologies researchers could take a snapshot of both rod and cone cell populations at various time points in the demise of the retina and get a ringside view of the activity of nearly 200 genes during various stages of photoreceptor cell death. When the data was crunched almost 35% of the "hits" showed activity in genes involved with cellular metabolism and one in particular, the insulin/mTOR signalling pathway, clearly stood out.

The insulin/ mTOR signalling pathway is known to be a critical pathway in regulating a number of aspects of cellular metabolism and its identification in a global gene expression assay of dying rod and cone photoreceptors suggested that there may be a link between the pathway and cell death. Under normal conditions the mTOR protein interacts with several cell proteins to facilitate high-energy processes such as protein translation. However, under conditions of stress, such as nutrient deprivation, mTOR has the opposite effect. Dr. Cepko and colleagues observed that the active mTOR was progressively reduced in the retinas of the four RP animal models and that its depletion coincided with cone cell death. This certainly appeared to be a smoking gun but a clearer understanding of the mechanism would be required before all the dots could be joined together.

The observations around mTOR activity suggested that a nutritional imbalance, possibly caused by reduced glucose levels, was occurring in cones during

RATHEACHIEVERP a g e 7 RETINA AUSTRALIA (VIC) INC. degeneration. In support of this model additional assays showed the transcription factor HIF 1 (hypoxia inducible factor 1) and its target, GLUT-1 (glucose transporter 1) were up-regulated in the cone photoreceptors of all models, which is what one would expect in cells trying to overcome nutrient deprivation. A further consequence of such nutrient deprivation would be the activation of "autophagy" in which cells re-absorb proteins and organelles in an effort to retrieve cellular nutrients. One form of such autophagy, "chaperone-mediated autophagy", or CMA, can be detected by the expression of CMA related genes in dying cone cells and this is exactly what was found in each of the RP animal models. Now several lines of evidence were pointing to the idea that cone cells in the degenerating RP retina may be dying from starvation brought about through compromised glucose uptake and low mTOR activity.

The next obvious step, once it was found something was missing, was to re-introduce the putative missing part and see what happens. When one of the animal models of RP was administered with insulin over a 4-week period cone cell survival improved. It appeared that facilitating glucose uptake ameliorated cone cell death. Taken together these observations provide an entirely new mechanism for explaining cone cell death in RP, not to mention the identification of a potential pathway to target for the development of new therapeutics.

The model for resolving the mystery of healthy cone cell death may also prove to be remarkably elegant in that it simultaneously accounts for why cone led pathologies do not lead to rod photoreceptor cell death. Given the role of the retinal pigment epithelium (RPE) in shuttling nutrients and oxygen from the choroid to the photoreceptors the Harvard model of cone cell demise via starvation is entirely reasonable when one considers the number of rods to cones in the human (and mouse) retina.

As approximately 95% of human photoreceptors are rods and approximately 20-30 outer segments of photoreceptors connect in with one RPE cell, a simple calculation shows that possibly one or two of the RPE/outer segment contacts are with cone cell outer segments. As the retina degenerates the outer nuclear layer (ONL) breaks down and consequently the number of RPE/cone connections becomes less. Dr. Cepko and her team suggest that as the number of RPE/cone connections falls below a certain threshold required for proper flow of nutrients the reduced supply of nutrients to the cones leads to cell starvation. In other words cell density may represent a critical threshold and it may be no coincidence that in all four models of RP, cone cell death occurred when there was a single layer of rods remaining in the ONL.

The mechanism of cone cell death proposed by the Harvard researchers also neatly explains the "reverse case", i.e., why the loss of cones in a cone-led degeneration does not lead to rod photoreceptor cell death. Again, a simple look at the numbers show that cones account for less than 5% of human photoreceptors and, even when the majority of cones are lost, significant cell density remains from the rod cell population. In essence, the "critical threshold" is never reached in cone-led degenerations and so rods never experience a comparable starvation phase.

RATHEACHIEVERP a g e 8 RETINA AUSTRALIA (VIC) INC. While the simple administration of insulin in the RP animal models lead to cone cell survival it is unlikely that such a strategy could be advised as a human therapeutic approach. However, if the mechanism proposed by Dr. Cepko and colleagues for cone cell death in RP is validated, then there may be an abundance of therapeutic targets and opportunities available for medical intervention. Given the clinical and genetic heterogeneity of RP, the commonality of its final phase may provide an attractive opportunity to treat a very large market and extend the viability for fine and colour vision even as the rods are lost. Source: Temple House, Dublin, 1 October 2010.

Green Tea May Ward Off Eye Disease Substances found in green tea work their way into the tissues of the eye and could protect against common eye diseases like glaucoma, researchers say. The findings, published in the current issue of the Journal of Agricultural and Food Chemistry, suggest that the substances, known as catechins, are absorbed by the lens, retina and other parts of the eye. Catechins are antioxidants thought to protect the body against damage from oxygen. "Our results indicate that green tea consumption could benefit the eye against oxidative stress," the authors said. Source: American Chemical Society, News Release, February 2010

Zhang and co-principal investigators Sheng Ding, PhD, from The Scripps Research Institute, and Thomas Reh, PhD from the University of Washington, received the highest possible scores for their proposal to investigate the regenerative potential of retinal cells, resulting in a $4.66 million NIH Transformative Award. Their long-term goal is to restore visual function lost through diseases such as macular degeneration and retinitis pigmentosa.

"The success of this work could mean a paradigm shift in how retinal disease is treated, and could have broad and profound impact on human disease therapies by utilizing the regenerative power of our own cells," said Zhang.

Some vertebrates, such as goldfish and newts, have a remarkable ability to regenerate a lost limb or eye - something it was thought no mammal can do. However, they recently showed proof of principle at a small-scale level in mice by turning Muller cells into a type of retinal neuron.

"The human genome is quite similar to that of a newt, but we humans seem to have lost the potential to regenerate our own cells, possibly due to some inhibitory

RATHEACHIEVERP a g e 9 RETINA AUSTRALIA (VIC) INC. mechanisms," Zhang said. "We are seeking small molecule chemicals that can block these inhibitions and consequently unlock humans' regenerative potential."

The researchers are looking at particular kinds of cells called Muller cells, which are abundant and have the ability to regenerate nerve cells after retinal injury in fish. They usually play a supporting role in the central nervous system neurons of humans, such as those present in the eye or brain. This study proposes to use chemicals to turn Muller cells into photoreceptors in the eye - cells that are lost in two diseases that are leading causes of blindness, macular degeneration and retinitis pigmentosa.

Identification of chemicals for Muller cells reprogramming and differentiation will provide new avenues in developing cell-based therapy as well as small molecule drugs for regenerative medicine, and facilitate new understanding of the mechanisms of trans-differentiation, according to the scientists. They plan to screen more than 100,000 compounds in order to identify the chemicals that prompt mouse Muller cells to develop new neurons, conferring the power of regeneration to the mammalian retina.

Source: Opthalmic Times, 5 October 2010

Efficacy of Sustained Topical Dorzolamide Therapy for Cystic Macular Lesions in Patients With Retinitis Pigmentosa and Usher Syndrome

Objective To determine the efficacy of sustained topical therapy with dorzolamide hydrochloride, 2%, on visual acuity and cystic macular lesions in patients with retinitis pigmentosa and Usher syndrome.

Methods In a retrospective case series at a university hospital, 64 eyes of 32 patients with retinitis pigmentosa or Usher syndrome receiving treatment with the topical dorzolamide formulation for 6 to 58 months were enrolled. Changes in visual acuity on the Early Treatment Diabetic Retinopathy Study chart and central foveal zone thickness on optical coherence tomography were measured during follow-up for the duration of treatment.

Results Among the study cohort, 20 of 32 patients (63%) showed a positive response to treatment in at least 1 eye and 13 patients (41%) showed a positive response in both eyes. Four patients (20%) showed an initial response and a subsequent rebound of

RATHEACHIEVERP a g e 1 0 RETINA AUSTRALIA (VIC) INC. macular cysts. In 8 patients (25%), there was no response to treatment and the macular cysts worsened when compared with the pretreatment level. Ten patients (31%) had improvement in visual acuity by 7 or more letters in at least 1 eye at the most recent follow-up visit. Sixteen patients (67%) showed a reduction of more than 11% in the central foveal zone thickness in at least 1 eye when compared with the pretreatment level.

Conclusions Patients with either retinitis pigmentosa or Usher syndrome who received treatment of cystoid macular edema with topical dorzolamide followed by an optical coherence tomography–guided strategy showed a decrease in central foveal zone thickness in most cases. Visual acuity improved in almost one-third of the cases, suggesting a potential corresponding visual benefit.

Source: Mohamed A. Genead, MD; Gerald A. Fishman, MD, Arch Ophthalmol. 2010;128(9) ______D i s a b i l i t y W e b s i t e DiVine is a website written by and for people with a disability. The site is published by the Victorian Government’s Office for Disability in the Department of Planning and Community Development. DiVine aims to inform, engage, entertain and encourage participation. Check out DiVine at www.divine.vic.gov.au Italian Study for Experimental RP

In Retinitis Pigmentosa, progressive photoreceptor degeneration leading to blindness occurs through an active form of cell death known as apoptosis. This word, derided from Greek and referring to the process of tree foliage, is a complex mechanism, implicating a number of biochemical reactions, precisely controlled by the cell. Using the retinal degeneration 10 (rd10) mouse model of RP, a group of Italian investigators leaded by Enrica Strettoi, from the Italian National Research Council (CNR) and Riccardo Ghidoni, from the University of Milan, investigated the role of ceramide, a lipid molecule used by cells as a pro-apoptotic messenger, in retinal degeneration. The group of investigators tested the possibility that photoreceptor loss could be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. The experiments lead to the finding that retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Moreover, single intraocular injections of myriocin, a powerful inhibitor of the rate limiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive and long term treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Such noninvasive treatment lowered retinal ceramide in a manner

RATHEACHIEVERP a g e 1 1 RETINA AUSTRALIA (VIC) INC. similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting trans-ocular drug administration. Prolonged treatment (over 20 days) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Trans-ocular administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies. The study was published in the Neurobiology section of PNAS and was co-authored by Claudia Gargini, University of Pisa, and Paolo Gasco, from Nanovector, the Turin- based biotech who patented the nanoparticles used for delivery. Young investigators participated to the study. The research project was co-funded by the British Retinitis Pigmentosa Society.

Source: Neuroscience Institute, CNR, Pisa, ITALY BOOBOOK OWL BADGE NOW AVAILABLE $2.00 each Buy for yourself or take a box of 50 for sale in your local optometrist etc. Contact Lin for orders

Genable, a Foundation Fighting Blindness (FFB)-funded biotechnology company in Ireland, has used an innovative gene therapy to slow the progression of vision loss in mice affected by a dominant form of retinitis pigmentosa. The company is working toward a study of the treatment in larger animal models with the goal of launching a clinical trial thereafter.

Treating dominant forms of retinal degenerative disease with gene therapy is challenging, because the process requires two steps: 1) shutting down the defective gene; and 2) delivering a new, healthy gene. Genable’s treatment employs RNA interference (RNAi) to shut down the disease- causing gene.

A benefit of RNAi is its effectiveness regardless of the variation in the unhealthy gene. In the mouse study, Genable’s RNAi technology shut down the gene rhodopsin, which can have more than 100 disease-causing variations. RATHEACHIEVERP a g e 1 2 RETINA AUSTRALIA (VIC) INC. An adeno-associated virus (AAV) was used to deliver both the suppressive and replacement components of the treatment. AAV is the same delivery technology currently being used in landmark clinical trials of gene therapy that are restoring vision in children and young adults with Leber’s congenital amaurosis.

“ We are very encouraged by Genable’s progress,” says Steve Bramer, Ph.D., chief drug development officer with the Foundation’s clinical trial organization. “Their RNAi technology, its ability to suppress the unhealthy gene, overcomes a major hurdle in developing gene therapy for people with dominant forms of RP. Genable has made a big step forward.”

Results of Genable’s gene therapy study were presented at the XVIIIth Annual Congress of the European Society of Gene and Cell Therapy held October 22-25, 2010 in Milan, Italy.

Source: Foundation Fighting Blindness website, www.blindness.org

ReVision Therapeutics Inc. has announced that data from a Phase 2b trial show that fenretinide (RT-101) reduced the incidence of choroidal neovascularization (CNV, wet age related macular degeneration) by about 50 percent in patients with geographic atrophy (GA), the most advanced form of dry age related macular degeneration (AMD).

The data, presented by Alexander M. Eaton, M.D., at the Annual Meeting of the American Society of Retinal Specialists, also showed a trend for reduced GA lesion growth rates in patients receiving fenretinide. These data suggest that fenretinide may have an effect on both GA lesion size as well as the conversion to the more sight- threatening wet form of AMD. Fenretinide is the first oral therapeutic to complete a Phase 2 trial in GA patients.

"These results are very exciting as there are currently no drug therapies for geographic atrophy, and there are no treatments for the prevention of CNV," said Dr. Eaton, who was an investigator in the trial. "We are hopeful that the complete analysis will further validate these findings as fenretinide could slow vision loss in the millions of people who face blindness because of this disease."

The double-masked, placebo-controlled, multicentre, Phase 2b study evaluated 246 patients with GA. Patients were randomised into three cohorts and received once-daily doses of 100 mg or 300 mg of fenretinide or placebo for 24 months. Retinal lesion size was measured by color fundus photography, fundus autofluorescence and fluorescein

RATHEACHIEVERP a g e 1 3 RETINA AUSTRALIA (VIC) INC. angiography. Patients were also evaluated by contrast sensitivity, reading rate, visual acuity, optical coherence tomography, and the incidence of CNV. Fenretinide was well tolerated with no severe drug-related adverse events and no significant effects on normal vision function.

At the conclusion of the two-year study, 15 of 82 patients (18.3 percent) in the placebo arm progressed to CNV, while 15 of 164 patients (9.2 percent) receiving fenretinide at either dose developed CNV. While the results were statistically significant (p=0.039), this was the result of exploratory and ad hoc analyses.

Preclinical studies show that fenretinide reduces the expression of vascular endothelial growth factor (VEGF) isoforms. These proteins are known to cause aberrant growth of leaky vessels within the retina and have been implicated in severe vision loss in patients with CNV. Fenretinide was also found to upregulate the expression of complement factor H, a potent inhibitor of the inflammatory pathway. Dysfunction or deficits in complement factor H are known to significantly increase risk for development of CNV. This preclinical data suggests that the anti-angiogenic and anti-inflammatory properties of fenretinide may underlie the reduced incidence of CNV observed in the clinical trial. The accumulation of retinol (vitamin A) derived toxins in the eye is believed to be a significant risk factor for the development of GA. The ability of fenretinide to reduce the delivery of retinol to the eye, and therefore reduce accumulation of these toxins, is thought to mitigate this risk. Analysis of GA lesion growth by color fundus photography showed a trend for slowing of lesion growth in patients receiving fenretinide. This trend was particularly evident in patients in the 300 mg dose group who had substantial reductions in serum retinol and its carrier protein, retinol binding protein (RBP). Data from the 300 mg dose group demonstrated a reduction in median lesion growth when RBP and retinol levels were reduced by more than 50 percent. This finding supports the proof of concept that reduction of circulating RBP and retinol reduces lesion growth in patients with GA.

Full analysis of all lesion size measurements is ongoing. The complete data will be presented later this year at the annual meeting of the American Academy of Ophthalmology.

Source: ReVision Therapeutics Inc, 1 September 2010.

The US Food and Drug Administration (FDA) has given the go-ahead for the controversial transplant of embryonic stem cells into the eyes of patients with Stargardt's macular degeneration, where the light-sensitive retina cells at the back of eye are destroyed. The announcement follows the first injection of embryonic stem cells into a patient in the US who is partially paralysed as a result of a spinal cord

RATHEACHIEVERP a g e 1 4 RETINA AUSTRALIA (VIC) INC. injury. Last October, a US biotechnology company, Geron, announced the start of the first clinical trial of embryonic stem cells with the hope of repairing damaged nerves. Another US biotechnology firm, Advanced Cell Technology, has now been given approval for a second clinical trial involving the injection of thousands of embryonic stem cells into the eyes of a dozen adult patients with a juvenile form of macular degeneration. Robert Lanza, the company's chief scientific officer, said that the first patient could receive the stem cell transplants early in the new year and although the trial is designed primarily to assess safety, the first signs of visual improvement may be apparent within weeks. "Talking to the clinicians, we could see something in six weeks, that's when we think we may see some improvements. It really depends on individual patients but that's a reasonable time frame when something may start to happen," Dr Lanza said. Embryonic stem cells, which are derived from IVF embryos just a few days old, have the ability to develop into any of the dozens of specialised cells of the body. Researchers believe they could revolutionise medicine because of their ability to repair damaged tissues and organs in situ without the need for whole-organ transplants. Dr Lanza said that the clinical trial on patients with Stargardt's disease will involve several clinics across America, including the Casey Eye Institute in Portland, Oregon, the University of Massachusetts in Worcester and the New Jersey Medical School, Newark. The first three patients will receive injections of 50,000 embryonic stem cells, the second set will receive 100,000 cells and the highest dose will be 200,000 cells. Animal studies have shown dramatic improvements in eye sight following the lowest dose, Dr Lanza said. "We've tested these cells in animal models of eye disease. In rats, we've seen 100 per cent improvement in visual performance over untreated animals without any adverse tumors or other side effects," he said. "These cells have been really performing quite spectacularly in the animals. If we can see that in the human patients we will hit a home run here," said Lanza.

The 12 people in the initial study will have an advanced form of Stargardt's disease and do not expect to have their vision restored, since the test's main objective is to gauge safety. If ACT's trial shows that the treatment is safe, the process would be eventually be tested on younger patients to see if it can prevent blindness. Scientists say the use of embryonic stem cells as a treatment for cancer and other diseases holds great promise, but the process has drawn fire from religious conservatives and others who oppose it. Embryonic stem cell research is controversial because human embryos are destroyed in order to obtain the cells capable of developing into almost every tissue of the body. Patients with Stargardt’s disease often experience blurry vision, difficulty seeing in low- light and eventually lose much of their ability to see at all. The disease can be inherited by a child when two parents carry the gene mutation that causes it.

RATHEACHIEVERP a g e 1 5 RETINA AUSTRALIA (VIC) INC. "This is a horrific disease that affects children starting at age six. The hope would be to treat patients earlier to prevent this from happening at all." said Lanza.

Source: Steve Connor, Independent Science, 22 November 2010 ______

What is Optogenetics?

Optogenetics is so new a field that many scientists are still learning what it means and how it works. Brain scientists are a little ahead. They have begun applying it to animal models of depression, narcolepsy, schizophrenia, autism, Parkinson’s disease, addiction, and memory. Optogenetics is a technology for controlling the “on-off” of neurons; in other words, for triggering or quelling action potentials within groups of nerve cells or in individual nerve cells. It uses a combination of light sensitive proteins (opsins) and pulses of light of different wavelengths to trigger or depress depolarization of nerve cells. Optogenetics was pioneered and named by Karl Deisseroth, a psychiatrist and optical neuroengineer at Stanford University. Since then, Swiss, Germany, and French collaborators have reported on how they are applying optogenetics to cone photoreceptors in mouse models of retinitis pigmentosa and activating retinal circuit functions. Source: The ARVO Report, 2010. Understanding Stem Cell Therapy PART TWO

In the Spring edition of The Achiever we published Part One of this three part piece on Stem Cell Therapy which covered what stem cells are and the various types. In this issue, we review the early developments of stem cell research since its inception in 2000. In the final part to be included in the Autumn 2011 edition, we bring the stem cell research developments up to the present day.

2000 It was discovered that stem cells have certain characteristics of photoreceptor cells. This was reported by Dr. Derek van der Kooy (University of Toronto) and Dr. Iqbal Ahmad (University of Nebraska).

2001 Researchers showed that transplanted cells from a mouse retina were able to reproduce, and that some of them contained the photoreceptor-specific protein, rhodopsin, which initiates the visual cycle (phototransduction).

2002 Scripps Research Institute in California reported success in forming new retinal blood vessels in mice with ocular disease. The process uses pluripotent adult stem cells derived from bone marrow and injected into the vitreous of the eyeball.

RATHEACHIEVERP a g e 1 6 RETINA AUSTRALIA (VIC) INC. 2004 Embryonic stem cells were engineered by Advanced Cell Technology in California which could be used to repair a damaged retina. The results illustrated the need to use cloning technology to eliminate the risk of rejection by the patient’s immune system.

2004 Researchers at the University of Toronto cultured and transplanted stem cells from human retinas into the healthy retinas of young mice. After four weeks, most of the cells had migrated to the new retinas and successfully differentiated themselves into photoreceptor cells.

2004 Scientists from Harvard’s Schepens Eye Research Institute successfully, and for the first time, improved the vision of mice with transplanted progenitor stem cells from day-old mice. This procedure had preserved existing cells and restored health to those that were degenerating.

2006 Work with humans began. A research team in India reported that 50 patients severely affected by age-related macular degeneration or retinitis pigmentosa showed significant improvement in vision after one month of injecting stem cells, and that there was further improvements after a gap of three months. 5. What makes you angry? 2006 Researchers at the University of WashingtonDropping used anything a mix of and growth not being factors to coax embryonic cells into becoming retinalable cells. to find Thisit – a wascommon the firstRP use of human stem cells using the technique for theproblem! retina.

Question Time6. What’s the hardest thing with Joan Parkeryou’ve ever done? Giving up driving and losing some In this edition, Joan Parker has kindly agreedindependence. to volunteer for Question Time.

7. What’s the best thing you’ve ever done? Have confidence in a guide dog.

1. What’s your earliest memory? 8. What do you like about Retina Four years old with parents, camping Australia (Vic)? and fishing in boat on a very wide river. The helpful information I can receive from them. 2. What’s your ideaSnow of a good time? Beautiful meal and lively conversation 9. If you could change one thing with my family. about the world, what would it be? 3. What’s your ideal holiday For people to have respect and destination? manners with others. The Greek Islands. 10. What’s the most important 4. Who inspires you? thing you’ve learnt about life? My youngest daughter, who is caring Keep busy and as independent as and helps solve any problems. possible. RATHEACHIEVERP a g e 1 7 RETINA AUSTRALIA (VIC) INC.

LAST WORD Alone we can do so little; Together we can do so much. I am only one, but still, I am one. I cannot do everything, but still, I can do something. I will not refuse to do the something I can do. HELEN KELLER, 1880 - 1968

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