The Retina International 2014 World Congress took place from the 27th to 29th June at the Pullman Montparnasse Hotel in Paris. The venue was centrally located in the historical heart of Paris on the left bank, close to the Eiffel Tower and Paris monuments and adjacent to the Montparnasse railway station.
During the Congress, French and International renowned scientists gave an overview of the latest medical advances in eye diseases. Sessions were dedicated to Retinitis Pigmentosa, Macular Degeneration, Stargardt’s disease, Usher Syndrome, Optic Neuropathies as well as other inherited retinal diseases. Information was provided about some of the clinical trials currently being conducted around the world and the perspective of future trials was discussed.
Overall this was an opportunity to learn about the latest research updates from the group of scientists present and to hear about their plans for the future. Some of the presentations also included reports of work being undertaken by colleagues across the globe.
This 18th Retina International Congress was officially opened by Christina Fasser the President of Retina International, Eric Moser the President of Retina France and Professor Jean Louis Dufier chair of the Congress Scientific Committee. It was very interesting to hear the professor welcome attendees in eight different languages including French, German, English, Spanish, and Chinese.
In her opening speech, Christina highlighted the fact that when the Retina International Congress was last in Paris, twenty years ago, only six genes for inherited retinal diseases had been identified whereas now there are over 250 genes identified and an understanding that more will be identified in the not too distant future. She also mentioned that clinical trials had commenced in 2006 and currently there are fifteen clinical trials being undertaken for different forms of retinal disease in various parts of the world, with plans for many more to come.
After officially opening the Congress, Christina Fasser presented a Retina International Special Recognition Award to Professor Dufier for his services to Retina France over many years, and his contribution to the Retina International and Retina France Scientific and Medical Advisory Boards, his lead role in research and his work as a clinical ophthalmologist.
A second Special Recognition Award was presented to Professor Jose-Alain Sahel who is renowned for bringing European retinal degeneration research onto the international scene and for his humanity and willingness to help the patients involved. In accepting the Award, Professor Sahel said that he was: “extremely honoured to receive the award, we make a choice, but patients do not, and we need to do the most we can to help. We do not always succeed but it is most important that we have tried”.
A summary of the sessions which were directly related to inherited retinal disease follows.
Conference Introduction – Inherited Retinal Disease
Professor Alan Bird – London
Professor Bird stated that he commenced his work on Retinitis Pigmentosa (RP) in 1969 with the knowledge that it was genetic; there was more than one form of the disease which could possibly be either dominant or recessive; it had a variable phenotype; it could be associated with multi-system disease; it involved rods in some way; the cause was unknown but a vitamin A deficiency could be linked; and there were other inherited retinal diseases which caused similar loss of vision.
Professor Bird spoke about the stages of discovery that he experienced. In 1982 he identified the relative prevalence of RP to be: 23% dominant; 56% recessive; and 21% x-linked. He mentioned that some of his original investigations were to determine whether RP was a rod dystrophy, a cone disease or related to photoreceptor loss, and how he found that the different types of RP could be affected by these three influences in very different ways. Professor Bird explained that his work involved providing a sequence for photoreceptor loss; identifying genes; relating phenotype to mutation and questioning whether the disease was the same for each mutation.
Professor Bird mentioned that the first RP gene was localised in 1984 and identified in 1989 and currently there are approximately 250 RP genes known with a hint of more to come. Professor Bird spoke about the fact that through researchers working together and, through the improvement in knowledge and technology, additional genes would be more quickly found and reminisced that it took five years to identify the first gene, after it was located. In the twenty five years since 1989, there have been in excess of 240 genes found, most of which have been found in the previous ten years.
Professor Bird said that he has undertaken lots of research into why some people who had inherited the faulty gene did not get the disease and spoke about biological therapies for inherited retinal diseases including:
- Gene therapy where there have been some successes today with the use of mice models, dogs, and human trials,
- Growth factors and
- Cell transplantation
Professor Bird concluded by saying that he is proud to have been a part of research work that has yielded results, been encouraging, combining clinicians, researchers and patients and he is excited with the promises for the future.
Syndromic forms of early RP, Leber Congenital Amaurosis (LCA) and Ciliopathies
Professor Helene Dollfus – Strasbourg
Professor Dollfus spoke about her work which involved the use of a fundus examination, through OCT imaging, or electroretinagram (ERG), to diagnose which specific disease the patient had. Professor Dollfus gave an overview of genetic diseases and of what a mutation means, and also spoke about the early onset of retinal disease, LCA or juvenile RP. She also mentioned syndromic manifestations where persons have a retinal disease and additional problems with organs, bones, obesity etc. In particular she briefly spoke about:
- LCA which was first described in 1869 but there are now a number of different forms of LCA which have been discovered. It was stated that all children with LCA have the same problems with their eyesight but those that have mutated genes in their ciliary genes may develop other symptoms
- Bardet Biedl (emblematic ciliopatgy) can also display obesity, supernumery fingers, cognitive disorders, renal and liver abnormalities
- Alstrom which usually combines some of the following symptoms -obesity, deafness, diabetes, cardiomyopathy, pulmonary fibrosis, growth hormone deficit
- Joubert Disease includes neurological problems
- Jeune Disease has skeletal and lung underdevelopment
- Senior-Loken Disease includes kidney malfunction.
Professor Dollfus believes that it is absolutely crucial that there is early diagnosis because of the potential for such difficult syndromes to develop and these symptoms should be treated at an early stage. She described the different types of therapy options for research in brief, referring to the fact that many would be explained during the remainder of the meeting.
Professor Dollfus concluded by stating that she was very hopeful that in the years to come the researchers will find a treatment for all of these diseases.
Pigmentary Retinopathies and its clinical aspects
Professor Jean Louis Dufier – Paris
Professor Dufier spoke about clinical heterogeneity, genetic heterogeneity, differential diagnosis and clinical genetic markers. He also explained the various forms of RP and how they affect people who have these diseases. Much of his talk involved an explanation of the heredity patterns, using diagrams and pictures of the eye showing the differences between affected and non affected vision.
This was a very good explanatory session for those delegates who were first time attendees and was delivered in a noncomplex way.
Other retinal degeneration – what’s new in Stargardt macular disease Professor Robert Koenekop – Montreal, Canada
Professor Koenekop explained the various forms of Stargardt disease, its inheritance pattern and the methods used to identify this disease in children. He stated that this disease was first discovered in 1909 through a study of 7 families by researcher Carl Stargardt. Nowadays it is believed that 1 in 10,000 people carry the gene, which is autosomal recessive, and children usually display symptoms of this condition and diagnosed by the age of ten.
Professor Koenekop has discovered through his studies involving Canadians, French Canadians and Chinese patients that there are different mutations in patients with different nationalities. He also said that 60-70 % of patients have ABCA4 mutations whilst others have PRPH2 (RDS), CRP1 or BEST mutations.
Professor Koenekop showed photographs of the retina of various patients to explain the differences between the clinical diagnosis of various forms of Stargardt’s and other retinal diseases which had at first been diagnosed as Stargardt’s. He spoke clearly about the patients who are eligible for the clinical trials of Stargardt disease and that the several trials being undertaken currently involving the consideration of different treatment options which include:
- replacing the gene and the protein;
- replacing the cells through stem cell therapy;
- considering the toxic build up;
- preventing cell death;
- providing alternative vision such as a retinal chip or
Professor Koenekop mentioned that a goal is to prevent accumulation of toxic retinoid intermediates and an example of a clinical study which considers this uses “Deuterium Enriched Vitamin A”. Another approach cited is to use the retinal binding protein 4 (RBP4). There are currently two active clinical trials in Paris where the gene is being replaced by surgery with an objective of halting the disease. Professor Koenekop said that cell replacement is more difficult and more politic but in Stargardt’s, cells are lost so to replace them is more possible than for other diseases.
Overall Professor Koenekop was extremely confident that there will continue to be significant advances in the future and that there are promising treatments for Stargardt’s in the pipeline.
Current tools for clinical diagnosis : autofluorescence, ERG, adaptive optics, OCT
Assistant Professor Isabelle Audo – Paris
Assistant Professor Audo listed the many different methods of clinical diagnosis, including the fact that many questions need to be asked about the person’s lifestyle and what type of problems they have in getting around, how various light conditions affect them, and whether day or night was more of a problem. She also mentioned that genetic aspects were very important and it was crucial to put together a family tree for each patient.
Part of Assistant Professor Isabelle Audo’s presentation included the assessment of the level of disability for driving (undertaken in France) and explained how difficult it was to perform “field tests” thus requiring a necessity to have additional methods of testing to ensure that a correct diagnosis is made. She went on to say that autofluorescence tests were slightly complicated because you need to be able to read the results but they are not painful for the patient and can lead to a much more informed diagnosis.
This presentation included an explanation of the various alternative diagnostic tests available, namely autofluorescence, ERG, adaptive optics, and OCT. There is a strongly held belief that all methods of diagnosis should be used with patients who are being considered for inclusion in clinical trials to make sure that they are in fact the right people for the trial – that is they actually have the form of inherited retinal disease being studied.
Visual results with a retinal implant in an international multicentre trial
Dr Katerina Stingl – Tubingen, Germany
Dr Stingl spoke about her work with the implant which is called “Alpha IMS” and which is inserted sub- retinally. She explained how the implant was placed internally and showed a video of how a person with the implant would use the device.
The aims of the experiment were to provide:
- Visual acuity of 20/250
- Grey shades
- Visual field of 10 to 15 degrees
- Manual adaptation of contrast/brightness
- The restoration to some very low vision for persons completely blind
Dr Stingl also mentioned that these trials started in 2010 in a multicentre trial involving 29 participants from Tubingen, Dresden, London, Oxford, Budapest, Singapore and Hong Kong. The results to date are that 17 participants gained some light perception; 14 participants actually regained some acuity; 13 participants were able to recognise some objects from daily life; 8 participants actually explained the location of objects; and 8 participants reflected no change whatsoever.
The Argus II Retinal Prosthesis System
Symposium Second Sight
This session was chaired by a representative of the company Symposium Second Sight. He proceeded to ask very directed questions of three of the participants of the trial of the Argus II implant system and interrupted each speaker if they were giving too much detail. All three were discussing their experiences as patients five years into the trial, and although some of the discussion centred on how much better the Argus II prosthesis was compared to the previous version Argus I, there was no criticism about the Argus II at all. Given that the Argus II product has been approved for sale in America and Europe, this presentation was pitched at selling the devices. Delegates were encouraged to visit the “Second Sight” display stand to discuss their options and talk with the participants of the trial personally.
New mutations and genetic identification methods
Dr Jean Michel Rozet – Paris
Dr Rozet commenced his presentation by stating that 30 years ago we knew nothing about how many genes for inherited retinal diseases there were or even that there were mutations. We now know that there are more than 250 genes identified with 1000s of mutations. RP is a unique disease because even in families you can have different genes or phenotypes for different family members. He said that sometimes these genes can be dominant or recessive, and often the retina was involved with many different types of disease.
Dr Rozet stated that studies of these diseases are enormously complex because for some patients you would look at vitamin A levels and for others you look at signals to the brain. He mentioned that in the future we may even be able to give a genetic diagnosis for a foetus but this would rely on a very clear genetic diagnosis, and this would be complex and expensive.
Dr Rozet explained that he used Sangers sequencing tool, but this can only investigate 1000 genes at the one time. However the cost of Exome gene screening at 1000 euros each test is too expensive. Dr Rozet believes that if this cost is reduced to100 euros it will be a much more affordable solution and enable labs to identify genes more quickly and accurately. He went on to explain that for sequencing to be optimised, one needs a specific strategy with a study of candidate genes and a whole genome of reliable data.
Dr Rozet concluded that it was up to a geneticist to determine the most appropriate strategy to find a result in accord with the findings of the molecular biologist but they may not be 100% correct. He emphasised that the provision of advice based on identification of genes is a matter for specialists as not every geneticist has the ability to do this correctly.
Therapeutic approaches: gene therapy and cell therapy
Professor Robin Ali – London & Michigan
Professor Ali spoke about his research which was published in the magazine “Nature 2014” earlier this year. He also spoke about his work in collaborating with the Kellogg Eye Centre at the University of Michigan which was a recent addition to his workload.
Professor Ali explained that Gene Therapy was generally planned to be used for treating early stages of disease whereas Gene Transfer was used in humans for therapeutic benefit. He stated that there has been an exponential increase in understanding of genetic disease in recent years and explained how genes could be delivered to the cells of the retina through a presentation of his laboratory work using mice as the initial subjects for the study.
Professor Ali said that the main challenge is to translate the successes with laboratory animals to safe treatments for humans. He then spoke about his work with Stem Cells which he believes may be used for treating advanced disease. This study which his lab are currently investigating is a regenerative strategy for many forms of retinal degeneration in which the main cause of irreversible loss of sight is the breakdown of photoreceptors. Professor Ali is confident that there will be solutions with respect to the use of stem cells in the future, however it will take some time to test these in the laboratory, prior to any human trials being possible.
Artificial Vision: implants and optogenetics
Dr Serge Picaud – Paris
This presentation contained a repeat of the information previously delivered about the Second Sight and Tubingen retinal implants.
Dr Picaud briefly spoke about his own experiments with primates which have successfully proven that vectors for optogenetics therapy can be injected.
Clinical Trials: why so long and so expensive
Dr Geraldine Honnet – Paris
Dr Honnet explained in detail that the reason clinical trials take a long time and are very expensive is because you need to have many people involved but above all you need to ensure that you follow the rules and procedures for undertaking clinical trials with humans. She mentioned that some of these rules were more restrictive depending on the country where the experiments were being undertaken.
Dr Honnet provided the following list as a basis from which to commence planning for clinical studies. Things she believes you need in place or understand the influence of include:
- Accurate patient information
- Promoters and
- World legislation for marketing
From diagnosis to therapy – the complex and stressful journey from disease onset to effective patient management
Dr Josseline Kaplan and Dr Andre Driben – Paris
This session was very difficult to follow as the two speakers came from different backgrounds. Dr Kaplan is a geneticist and Dr Driben a psychoanalyst. Both have been involved in working with patients who have a family history of x-linked disease and who were seeking advice regarding the possibility of terminating a pregnancy because of this family history. Apparently it is possible for this to occur legally in France.
Dr Kaplan spoke strongly about the need to get an accurate reliable and tactful diagnosis to ensure that there is a need to make such a life-threatening decision in the first place. Dr Driben spoke about working with the patient to ensure that they would not be traumatised forever if they did make such a decision to terminate the pregnancy.
Both clinicians recognised that each case was different and that you cannot provide a unique solution for their work or to give the same advice to all of the x-linked patients who were seeking assistance with their decision making.
Therapy Trials: lessons and promises
Dr Jaques Mallet
This short talk regarding Gene Therapy for the eye included a presentation about the various animal models which are being used as a precursor to human trials. Dr Mallet spoke about the widespread use of the mouse model as a starting point for experimentation; however as a predictor of human reaction it has been found that mice retinas are too small. As a consequence there have been many experiments using monkeys, dogs, donkeys, pigs and other animals. It has been found that although monkeys exhibit human traits, they are very difficult to work with and that in fact pigs are a better option as they are more placid and have retinas a very similar size to that found in humans.
Dr Mallet concluded his presentation by stating that huge progress has been made during the previous ten years and he is hopeful that the next ten years will provide even quicker progress and produce satisfying results for all participants.
Leber Congenital Amaurosis and 1-RPE 65 trials in France
Dr Gylène Le Meur – Paris
Dr Le Meur spoke briefly about the history of the RPE65 gene which was first discovered in 1993, and believed to be associated with rod-cone dystrophy, and of its direct link to Leber Congenital Amaurosis. She recounted her involvement with these trials which involved each participant having an injection of the replacement gene at two monthly intervals. Dr Le Meur has worked in close collaboration with Professor Robin Ali’s team in London.
At this stage, Dr Le Meur stated that the side effects of the injections were minimal, and that they were similar results to those found after an operation for retinal detachment, that is, some ocular itching but there was no eye inflammation. She found that the Vector used as part of the injection could be found in tears and blood for a minimum number of patients but this was of little concern.
Although there are no long term results available for the human trials, Dr Le Meur stated that the dog trials undertaken first were a good model for the phase one human trial and to date things are going well. The team is very pleased with the results so far.
Perspectives of other ongoing trials: Stargardt’s, Choroideremia, Retinitis Pigmentosa, MERTK, Usher, Achromatopsia
Professor Jose-Alain Sahel – Paris
Professor Sahel spoke about a number of trials that he is involved in, some of which are also in collaboration with the University of California, and these are listed below with his comments.
- Gene Therapy has been used to correct gene defects, and in the main it is replacement therapy for genes which are missing or which have become inactive over time
- Neuroprotection is being used for Rod Degeneration and Trophic factors for Cone Degeneration
- RPE65 and MERTK gene mutations have been treated in six patients where 3 people have improved results but it is early days yet
- Choroideremia has been treated using the protein “RAB” for 6 patients who have shown such significant improvement that they will shortly be commencing further trials
- X-linked project has approval for clinical trials but has not yet commenced
- Stargardt’s Disease was mapped in 1993 and cloned in 1997 with greater than 400 mutations found to date. STARGEN is the gene based therapy for the treatment of Stargardt disease currently being trialled
- The mutation of the ABCR gene has been investigated using mouse models and then a primate model, thus gaining approval for clinical trials in Portland, Oregon and Paris for patients with very advanced forms of the disease. There are 3 patient groups with varying levels of degeneration and to date there has been no negative effects. An ERG is used to determine the correct area for injection for these patients.
- Usher Syndrome (Usher 1B) is the most severe form of Usher. Work in this field started with a mouse model for the MYO7A mutation and the teams in Paris and Portland are also collaborating with these experiments. A portable apartment and street, has been built within the laboratory so that the participants can undergo realistic tests regarding mobility, in safety, without having to leave the laboratory.
Neuroprotection in Retinal Disease
Dr Matthieu Robert – Paris
Dr Robert explained that Neuroprotection refers to the relative preservation of neuronal structure and/or function. It is a widely explored treatment option for many disorders and aims to prevent, or slow, disease progression. He initially spoke about why you should use Neuroprotection for retinal disease as it has been shown to slow the death of “diseased” retinal cells. He stated that given not all mutations are known and, that there are a great number of mutations, scientists will need to invent the same number of gene therapies eventually. In the meantime Neuroprotection techniques could be used until such therapies have been developed. That is, an intermediate step or an additional form of therapy that will not compete with the eventual treatment or cure.
Dr Robert spoke about studies that have been undertaken with mice and which are now being trialled. The various types of neuroprotective treatments are listed below.
- CNTF has been used in two trials of humans with 65 and 68 patients respectively. There has been no recorded improvement yet, however another trial in Italy is using eye drops and hopefully there will be interesting results within a few years.
- Apoptosis inhibitors have been used for 21 RP patients who undertook injections 3 times a week. The results indicate that 62% of treated patients have shown improvement in their visual field.
- Calpain activation has been used to determine if this will slow cell death
- Nutriant supplements such as Vitamin A and Lutein studies have been going on for a long time. Vitamin A must be strictly controlled because of its toxicity. In 2004 Vitamin results were promising but not significant and in 2010, Lutein studies, were also promising but not absolute. Dr Robert stated that there is no clear evidence of the benefit of treatment with Vitamin A for people with RP in terms of the change in visual field but some ERG results indicated a slight change in visual acuity for a small number of participants in the trials.
- Replacement of “lacking surviving factors”. Animal models are being used with injections of Rdcv4 protein and the results are very promising. The team has accumulated lots of positive evidence but it has taken five years to gain financial support and so clinical trials that have been planned can now progress.
- Increasing Choroidal Blood Flow through the use of Unoprostone Eyedrops used for Glaucoma, have been trialled for 40 patients in Japan and these indicate some improvement at this stage but further trials will be undertaken before any conclusions are made.
Dr Robert firmly believes that treatments for inherited retinal disease will be found it is just a matter of time and lots of hard work for the researchers. In fact he stated that:
Gene Therapy = tomorrow (that is in the future)
Pharmacological Treatments = tonight (much sooner)
Neuroprotection = this afternoon (almost immediately)
In the meantime Dr Robert firmly recommends that people affected by retinal disease should: wear UN protection sunglasses; not smoke; have their cataracts removed; treat Intra ocular inflammation and Macular Oedema and be regularly checked for any associated ocular disease.
The Pharmacological Clinical Trials: an alternate to Gene Therapy
Professor Robert Koenekop – Montreal, Canada
In this presentation, Professor Koenekop spoke about how he chose to study Lebers Congenital Amaurosis (LCA) in 1995 and that since then he has discovered 20 mutant LCA genes which in turn have led to clinical trials and treatments for at least 7 of these defective genes. He clearly outlined the retinoid cycle and stated that his work had been assisted by improved techniques for diagnosis such as Optical Coherence Tomography (OCT) which uses light waves and other associated results indicated by photopluoresence and autofluoerescence. Professor Koenekop said that “today we can see in five minutes such results without taking the eye out – ten years ago this was not possible”.
Professor Koenekop then talked about the history of LCA specifically for patients with RPE65 and LRAT mutations and gave an explanation of how the world scientists are trying to slow the progression with a view to eventually stopping it. He mentioned that currently four studies are occurring with adult humans who had shown a very rapid decline in visual field after age ten. The treatment is using an oral drug, 9-cis Retinal or Retinouid which has been found to reach all dormant viable photoreceptors and RPE cells in both eyes. This drug was chosen because it was shown to “rescue function” in the initial experiments and tests with mice and then dogs. To test the side effects, the drug was initially trialled with 20 patients who had no sight problems, and it was found that after four days, four people had some instances of headaches and weeping eyes, but otherwise there was no problem.
The results of one of these trials will be published in “the Lancet” in July 2014 but some information was provided by Professor Koenekop as he was closely involved with the project. He stated that the trials involved 14 patients from 3 continents – half with LRAT and half RPE mutations who were given an injection on day 1, 4, 7, 14, 28 and thereafter at longer intervals. After two years, the following results have been verified.
- For one patient after day 7 there was an enlargement of visual field and this was increased at four months until after 19 months a robust field was noticeable, however after 26 months the field has started to decline
- Another patient did not respond at all to the treatment
- Visual fields improvement ranged from 28 to 683 an increase for 72% of those involved but only 16% had sustained visual field after 2 years
- 32 % of the trial group had sustained visual acuity after two years
- Functional MRI showed improvement for 13 members of the trial group
- Notable improvements in 10 out of 14 patients with respect to quality of life and activities of daily living.
Professor Koenekop concluded by indicating that future treatments are currently being investigated and these will involve a placebo controlled clinical trial to commence later this year.
Neuropathy Target Esterase, the primary target of organophosphate toxicity is mutated in several types of childhood blindness: implications for therapy and photoreceptor biology
Professor Robert Koenekop – Montreal, Canada
Professor Koenekop spoke passionately about his work in trying to find new genes causing childhood blindness and the follow up investigation from this genes discovery to treatment avenues. He believes that it is imperative that if you discover new genes you should then try and find a treatment to counteract the debilitating effect of the faulty gene.
Professor Koenekop stated that millions of people are blind from photoreceptor degeneration and researchers throughout the world are working together to ensure that they find all of the genes for every one of the Retinal Diseases.
In conclusion Professor Koenekop briefly explained his recent work in trying to find the gene PNPLA6 which causes Oliver McFarland Syndrome. Once everything is known about this gene, work will begin to try and find an associated treatment for the ten cases reported in the world who have this faulty gene and its associated short stature, long eye lashes and severe RP.
The future of Retinal Implants
Professor Eberhart Zrenner – Tubingen, Germany
Professor Zrennar mentioned that work on retinal implants was being carried out across the globe and that the investigations were at various stages.
- Two devices are currently on the market and they are the Alpha-IMS system that he is strongly involved with in Tubingen, Germany which has 42 recipients and the Argus II from Second Sight which is being used by approximately 30 recipients in the USA and across Europe.
- The PIXIUM device has been devised by a consortium from Germany, Switzerland and France and is currently in well advanced clinical trials in France.
- Devices in Australia, Boston and Stanford are in early stages of clinical trials.
Professor Zrennar explained in detail the different types of implants and the effectiveness of each and also spoke about “Module 2” the second stage device that his team currently have at trial stage which has to date resulted in some participants being able to recognise letters of the alphabet, door knobs and dogs.
Professor Zrennar concluded by stating that experts believe that eventually implants will provide useful vision for some people at low risk to their overall health. In the meantime the challenge is how to make a prosthetic eye that will increase visual resolution and field size, and secondly, how can such a device be made for children with the plasticity needed as the child grows into an adult so that there is no need to replace the initial device.
Conclusion and Points to Remember
Professor Joe Hollyfield – Cleveland, Ohio
Professor Hollyfield spoke about the presentations that had been delivered to the Congress in both the scientific and general sessions. His report included the following information which he had collated from the various presentations aforementioned.
- RP is a genetic disease but it is not a single genetic disease.
- Currently 259 genes which can be attributed to RP have been mapped and 219 have been identified.
- The genes involved for all forms of RP are not yet known and it is estimated that there may be in excess of 100 remaining to be identified.
- The genes currently missing will be the harder ones to be found.
- As new genes are identified it is highly likely that many will be recessive disorders with the genetic product missing therefore they have a better chance of treatment because the missing gene can potentially be replaced
Professor Hollyfield mentioned that there were a number of different treatment strategies, and these depended completely on the form of RP diagnosed. Consequently if rods are lost; Gene Therapy, Pharmacology or Trophic Factors could be a solution and if cones are lost; Stem Cell Therapy, Pharmacology or Trophic Factors could be a solution. If both rods and cones are lost then treatment regimens could include Optogenetics or Retinal Implants.
In summary, Professor Hollyfield mentioned that the goals for Gene Therapy are to replace the gene that is missing to restore visual function or to eliminate the defective gene and replace it with the correct gene. Currently there are 18 Gene Therapy trials underway in the USA, UK, Israel, France, Germany and Saudi Arabia for various forms of retinal disease including: RPE 65 and LCA, Stargardt’s, Choroideremia, Usher type 2b, Achromatopsia, Retinal Schesis and MerTK.
Professor Hollyfield also stated that there are currently two types of Cell Based Therapy, one being where stem cells are used to replace lost photoreceptors using induced pluripotent stem cells, or photoreceptors generated from patient’s fibroblasts and the second being to prevent photoreceptor degeneration. At the present time there is one clinical trial being undertaken which involves experimental studies with umbilical cord stem cells.
With respect to solutions using “trophic factors”, Professor Hollyfield acknowledged that Professor Sahel and his team had been working in this area for many years and that the Neurotrophic factor CNTF has been in clinical trials for some time with some very satisfactory results.
Professor Hollyfield mentioned that there are several promising retinal implants already being utilised and that investigations of improved devices are currently underway across the globe. It was recognised that such devices were only intended for people with profound blindness and no light perception and that a number of individuals already have had some useful vision restored by such implants.
Professor Hollyfield concluded his summary with a “take home message” about staying informed about new advances – after 2014. He said that all delegates should
- Be involved with their local or national organisation
- Follow new advances on the internet
- Ask their ophthalmologist for updates in research, specifically related to their own condition
- Stay in touch with Retina International
- Ensure that their national organisation is represented at the annual Retina International medical and advisory board meeting during ARVO week.
Professor Gerry Chader – Los Angeles, California
Professor Chader introduced his summary of the Congress as being “Research Perspectives and the promise of Clinical Trials for treatment of RP and allied diseases”. He spoke about the six different areas which can lead to the treatment of retinal diseases whilst taking into account the two different disease situations involved. It was clear from his presentation that Professor Chader clearly believed that the type of therapy which might be applied was directly linked to the specific form of retinal disease encountered and thus it was extremely important that individuals received an accurate diagnosis of their disease so that they could access appropriate treatments as they become available.
Specifically, when most, or all, of the photoreceptor cells do not function or are dead, treatments that replace the dead cells or replace their function could be: Cell transplantation, electronic prosthetic devices or Optogenetics. When at least some photoreceptor cells are still alive, treatments that prolong photoreceptor life and make them function better would include Neuroprotection, Antioxidants or Gene Therapy.
In more detail, Professor Chader explained:
- Photoreceptor Transplantation
There has been limited success in transplanting normal photoreceptor cells into the retinal diseased retina from a normal donor retina, but recently stem cells have been used for transplantation. Stem cells have the ability to develop into adult cell types including photoreceptor cells and so when transplanted they might be able to replenish the supply of photoreceptor cells that have died due to the degeneration. There are several examples of success with the use of stem cells in animal models and this has resulted in the plans for clinical trials using human embryonic stem cells. It is known that already embryonic stem cells are being used in clinical trials for Stargardt Disease and dry AMD.
- Artificial Vision
The use of an electronic prosthetic device to replace the function of dead photoreceptors has been a big success story in the restoration of vision with successful clinical trials and commercial products now available. Presently the Argus II is available for purchase and many other academic groups and companies, including those in Germany, Australia, Japan, Korea, Ireland and the USA, are working towards the commercial release of other types of retinal devices. It is known that technologies are being improved to allow for face recognition and reading ability.
This process involves the use of molecular engineering to insert molecules into retinal cells to make them light sensitive. This process is commonly known as “photoswitches” as it involves light signals being passed to the brain to distinguish whether it is a lights on or lights off situation. This work is in early development but gives hope for restoration of functional vision into the future.
This process is used to delay photoreceptor death and there have been a number of factors found that satisfy this requirement. The well-known factor is CNTF and this is renowned to help protect the sick photoreceptor cells but there are others including RdCVF which promote cell viability. The current Neurotech clinic is looking closely at effective treatments for the many forms of RP and dry AMD and they hope to be able to find solutions for every condition over time.
Experiments and trials have proven that the use of Antioxidants have delayed the progression of dry AMD and some forms of RP. Currently one product available is called “RetinaComplex” and others are being investigated. Until all of the clinical trials have been deemed successful it is best to simply “eat your vegetables” as these are one of the best sources of antioxidants known.
- Gene Therapy
This process involves the replacement of defective mutated genes with new, normal copies. There are different types of Gene Therapy available depending on the type of retinal disease diagnosed. Also clinical trials thus far have centred on LCA with its well-known RPE65 gene and the success of these trials will be the model for treatment of other types of retinal disease into the future.
Professor Chader summed up by saying that we are finally passing out of the scientific darkness and into the enlightenment of clinical trials. For scientists and clinicians there are now many opportunities to do meaningful and sight-saving work. For patients, this will lead to new therapies that will save and restore vision in all types of Retinal Disease. Either way it is an exciting time.
The Congress was officially closed by Christina Fasser, Eric Moser and Professor Jean Louis Dufier who individually thanked the various major contributors to the event. Eric Moser announced that more than 1000 people had attended the Congress from 52 different countries and that the 50 speakers had also come from various parts of the world.
In true Olympic style, the team who are currently planning the 2016 Retina International Congress in Taiwan were invited to address the meeting. Dr Lu the Ambassador for Taiwan in France officially invited everyone present to Taipei for the Congress which will be held from 8th to 10th July in 2016. This was followed by a musical presentation from a group of blind and low vision Taiwanese people who were accompanied by students from a medical college choir who acted as guides. The presentation was a song entitled “You are my Eyes” which was written by a Taiwanese RP patient who completely lost his sight by age 27. The song was dedicated to the young man’s mother who helped him to adjust to life without vision.