Innovations in ophthalmology – research on retina implants and gene therapies

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Professor Eberhart Zrenner’s research interests include many fields of physiology, pathophysiology and degeneration of the retina, ophthalmology, neuro-ophthalmology, retinal implants, electrophysiology and many other non-invasive methods of non-invasive examination of visual functions. Since 1989 he has been the head of the Department of Ophthalmology at the Institute of Ophthalmological Research of the Ophthalmology Center of the University of Tuebingen. Before becoming one of the world’s leading authorities in ophthalmology, he also studied electronic engineering at the Technical University of Munich, which was an inspiration for future research work.  Jolanta Czudak talks to Professor Eberhart Zrenner about the unusual combination of two professions in scientific work, which are the source of international success.

 What is the background of your retina implant research?

EZ: It stems from my early youth, I was always fascinated by electronics, had built radios and wanted to become an engineer. I studied electronics and Engineering at the Technical University of Munich but found out that the brain is the best electrical system for processing information. Therefore I changed to medicine and became a medical doctor and an Ophthalmologist, as most of our information come through the eye to the brain. However, in parallel, I had continued  studying electronic engineering. as a hobby.

Having finished medicine,  instead of continuing with a residency at a hospital, I started working as a basic scientist at the  Max Planck Institute for  Sensory Physiological Research, recording electrical potentials from the human visual cortex and the human eye.  In 1977-1978, at the National Eye Institute in USA,  recording from single cells in monkey retina, I studied the retina, the circuitry of electric connections  responsible for processing  every image and  published a lot on retinal image processing. Studying living neurons in the retina was my second important experience: hrough a non-invasive manner of recording electrical signals from the human retina, I was attempting to understand how the circuitries in the retina function. I did a lot of research in this field and had already finished my “Habilitation” as physiologist when beginning the residency in ophthalmology. In 1985 I became an ophthalmologist. In that year I got an associate professorship for retinal studies, established by the Max Planck Society at the Eye Hospital of the University of Munich; in 1989,  I got the  chair of ophthalmology  at the Tübingen University dedicated to Pathophysiology of Vision and Neuro-Ophthalmology. From that time on, I was enjoying all the possibilities of a full-fledged Research Clinic.  We did not have an Institute in Tübingen at that time, but in parallel I built a research unit called “Forschungsstelle für Experimentelle Ophthalmologie” and in 2007, it was upgraded to an “Institute for Experimental Ophthalmology” where I became the Founding Director.  Meanwhile it has developed into a huge institute with  110 employees fully engaged in  ophthalmic research,  as part of a Department of Ophthalmology that  also houses one of the major eye hospitals, the only one in Germany where a research institute and an eye hospital are combined in the same building.

So why is this all important for the ratinal implant?

In 1994 the German Ministry of Health and Research asked: If deaf people can regain their hearing with electronic implants, why  not attempt to create a similar electronic implant for the blind? I was at that meeting and when the  German Federal Department of Research in 1995 provided a major grant for developing such an electronic vision implant, I applied together with several colleagues. Developing a retinal implant  ntended to let blind people regain some sight, you need  a very diverse team including physicists, material scientists, surgeons for developing a totally new surgery, you need scientists who do animal experiments and of course electronic engineers who do electronic circuits. There are  probably only very few people who would be equipped to lead such a very diverse group of scientists necessary to cooperate in creating an electronic implant.

Thanks to my personal interest, I was familiar with the different “languages” used by the various disciplines and able to speak with the electronic engineers in Stuttgart about circuits and amplifiers, to speak with physiologists, physicists at the Natural and Medical Sience Institute in Reutlingen, ophthalmic surgeons, and to some extent I could speak with material scientists and of course with the patients. I knew where to put an implant optimally into “the retina” because I had studied the retina for 15 years at the Max Planck Institute and at  the National Eye Institute in Bethesda.   Having recorded from single cells, I knew that  the implant would have  to be placed subretinally and not epiretinally.

We met every six weeks in my Department for almost ten years (1995-2005) and I had the opportunity to guide our SUBRET-group in developing the implant. Of course we went through several generations of implants. We started to try it out in  rabbit and pig and we tried several designs that failed to work, because we had to find an implant  small enough to be put in the eye but large enough to provide a sufficiently large visual field. We had to design an implant that produces sufficient  current  for stimulating cells but not too much current  in order to protect the cells. We had to learn in vitro how much current was needed and how much current was too much for the eye and would damage cells in the long run. We worked in pigs and recorded from the  pig cortex  to see whether the animal can see something. It was very exciting: The pigs with an  implant  briefly lifted their head and looked up from their feeding-trough when light was flashed,  but that was all we knew at that time. So we were encouraged to start in human one day, and after we had performed eight years’ of cortical recordings from pig and cat  (1995-2003,) we knew exactly what to do in the human. We had learned that 3 x 3 mm is the right size which would furnish 10° – 15° of visual angle We knew that with 1.600 pixel we could produce a useful image. We learned how to place it in a delicate surgery under the retina and we had the engineers able to build what was required. It was finally the 8th improved chip-generation that we used for starting the human pilot trial. It was very exciting when already the first patient was able to tell us — when we stimulated a row of electrodes representing a vertical line or a horizontal one. Therefore we knew that it was principally possible to restore some vision and we started a pilot clinical trial in 11 patients. At the beginning, the power supply was cable-bound, with a cable that was still coming out of the skin behind the ear (1995-1998): One patient really very important for us was Miikkaa. He was the one where we had put the implant first time right beneath the fovea; he could read letters of 8 cm in size and he told us that we had made a spelling error in writing his name. He said “my name is Miikkaa but with two “i” and two “k” and you have written it only with one “i” and one “k”.“. We have a movie about that in the internet. It was very exciting to know in principle that restoration of reading was possible. That allowed us to further develop the implant.

Until that point we had received all our funding from  the Federal Republic of Germany but now our government said  that we were so near to the market that according to European rules government could give us only 50% of the required funds. We were asked to come up with 50% private money because government funds only research but not business and marketing. We were very desperate at that time. How to get 50% of private money? Although we had the implant, the patients and everything else necessary, we could not start the clinical trial without full funding of it. Therefore we founded the Retina Implant company to start the clinical trial (now called “Retina Implant AG”) to be attractive for private funding. An American group initially wanted to fund us, but did not come up with the required funds in time;  then we found a German investor who helped us to further develop the concept and so we could start  the crucial clinical main trial in 29 patients. The implant meanwhile was no longer cable-bound  but worked with a subdermal cable that ran from  the orbita to the ear and had a coil under the skin behind the ear like a Cochlear implant. The signals for control of brightness and contrast as well as energy were transported through the skin by two coils; one receiver coil under the skin and another sending coil on top of the skin,  kept closely together by magnets.

What were the results of this research?

The results in 29 patients were published in one of the most respected scientific British journal, “The Proceedings of Royal Society, London” and we showed that approximately half of the patients had a benefit in daily life tasks from our subretinal implant. But we had a problem: the implant was only working for less than a year, maximally one and a half years, which was too short for recommending it to patients. Therefore we stopped producing this implant and built another one. The new version Retina Implant Alpha AMS, was available in 2012 and then we started a third trial with an implant that used new materials, better connection techniques, better cables. It had been tested in 65° C salt water with a machine that  shook it  a million times for  several months. We found out that in comparison with the previous implant it should have a five times longer lifetime. The new implant Alpha AMS has now been implanted in a series of patients already for more than five years like the early time hip replacements of the cardiac pace-maker had a lifetime of approx. five years and it can be replaced. It got the CE mark registration as a medical device in 2015 and entered the market that same year. In Germany, reimbursement by the German Healthcare System was achieved in six centers, i. e. the public health insurance coverage. Subsequently it was distributed also in France, Italy and in other countries. Of course vision with 1.600 pixels is not so high in resolution  that you could drive a car or see  details of  what is happening on the television system but many patients with Retina Implant Alpha AMS can find a cup on the table or a spoon, knife, they can see that a person is in front of them, whether somebody wears glasses or not. Some patients can see that somebody laughs because bright teeth are visible. Meanwhile enormous investments were made to develop the implant within the last 24 years. It turned out that unfortunately the expectations of most patients are much higher and hindrances for reimbursement process are manifold. Although the subretinal implant was implanted altogether in more than 70 patients,  too few were sold in the past two years to allow the company Retina Implant AG to continue production. Therefore no further subretinal implants are available at present.

 The Department for Ophthalmology in Tübingen is a leader in ophthalmic innovations, also in gene therapy and, Prof. Zrenner, do you think that there is a future in international cooperation to develop new gene therapies to make gene therapies available worldwide and how important is international collaboration?

There are more than 300 genes in which mutations can cause retinal dystrophies and gene replacement therapies have to be developed individually for each of them. There is not one single institution or company that can do that for all of the mutations that cause patients to lose their sensitivity to  light and become night-blind; then the visual field  narrows and many  patients  finally become blind.

I think it is extremely important to have international collaboration because the inherited form of retinal degeneration is relatively rare and development needs clinical trials, where hundreds of centers have to be involved. One in 4.000 European citizens is affected but each eye doctor sees only a handful of patients in his or her  lifetime. Therefore it is important to have  specialized centers. In Germany we have approximately six such centers specialized in caring for patients with hereditary rare retinal diseases. The situation is similar in all countries. Therefore, three years ago, the European Reference Network (ERN-EYE) was founded to cooperate across borders in patient care and research including Lublin University Eye Hospital in Poland where Prof. Rejdak is an excellent longstanding cooperation partner. This helps enormously in making new therapies available for patients with inherited retinal diseases. The good thing is that gene replacement therapy is being developed for patients with monogenic inherited retinal diseases. This is a development that started in early 2000 and very recently the first gene therapy has become available for patients with a special form of early hereditary disease, so-called “Leber’s Congenital Amaurosis.” The first gene replacement therapy  has been approved by FDA and EMA and it will now  be available to patients with this particular form of hereditary retinal disease. To be able at present to do gene replacement therapy,  to stop the disease,  to recover some of the photoreceptors and to protect the still functioning photoreceptors, is a very fantastic new possibility. Worldwide there are at least 30 if not more clinical trials going on right now, where this gene replacement is done.

How does it work?

A small amount of liquid that contains so-called adeno-associated viruses is injected beneath the retina. These viruses are not pathogenic, i. e. they do not produce a disease, but they enter the cells and deliver “cargo” into the photoreceptors or into other cells in the retina, depending on what cells they have been made sensitive for.. Their cargo is the intact piece of genetic information  the particular patient is lacking, . As a result, the cells are able to produce the correct protein. The positive effect was shown in the first marketed and registered drug for Leber Congenital Amaurosis, Luxturna. We are the only center in Germany that does gene therapy trials at present. We cooperate with centers in Oxford and in Paris but we have also developed our own gene therapy trial for Achromatopsia, for Retinitis Pigmentosa, PDE6A and we are part of several other consortia that develop gene therapy. This is a quickly expanding field where we need to find the patients, select the patients, to train the surgeons how to inject the viruses into the eye.. Through the European Reference Network we are in a process where we distribute this knowhow and hope to help many patients. Gene therapy is for patients who  still  have vision because we can treat only those patients who still have the diseased cells in order to rescue them by gene replacement therapy while the electronic implant is for people who have lost  all vision. Gene replacement therapy should not be confused with CRISPR/Cas9 gechniques, also called “gene scissors” or “gene editing”. This is not available to patients yet as safety issues are still to be solved and that will take many more years. You may have heard from these experiments that a Chinese colleague has done in two girls, changing their  inherited genetic make-up. This is unethical and banned in Europe and in the USA. Nevertheless there are currently many great developments that make ophthalmology  one of the most interesting  and promising disciplines in medicine at the forefront of new developments.  In gene replacement therapy  for the eye we can see exactly  what we are doing, looking through the pupil at the retina; the amount of viruses we need is small because of the very small amount of retinal tissue ; another positive aspect is that the eye i is a closed compartiment. Ophthalmology is the key discipline for a gene therapy and that is why we are so happy to be ophthalmologists right now

We are very grateful that Prof. Zrenner supported the involvement of the Department of Ophthalmology in Lublin in a European Reference Network for ophthalmic diseases. What role can we in Poland play for the European community and for this system?

It is very clear that gene therapy can  be applied only in very well educated and specifically trained centers that have access to these particular patients, who are equipped to perform   special function tests, who have the surgical skills to master such novel approaches..  Lublin is a very special and very well suited place for such developments, it is not only a national center for trauma in Poland, where the most difficult surgeries in some of the trauma patients are routinely performed.  so that Lublin has doctors with great surgical skills, and additionally, there exists  a longstanding cooperation of almost  20 years with our Tübingen hospital and a strong involvement in our research projects. Prof. Robert Rejdak started here 18 years ago and we had approximately 10 or 12 co-workers from Lublin joining our teams here over the years. During the last 15 years we had many Lublin residents here in the laboratory as well as in the clinic. At present we have PD Dr. Katarzyna Nowomiejska from Lublin here. She came every month last year for one week and even this year she will come so to see the various procedures. We provided the contacts to do the genetic analysis, and I think that within the European Reference Network there will be funds from Brussels that allow ERN centers to cooperate. At present there are 16 centers in Europe,  one in Poland, and that is in Lublin; three are in Germany and twelve more in other European countries. These centers are already particularly enabled  for transnational trans-border treatment of patients. Presently funds from Brussels are limited;  it is of course expected that the national healthcare systems would be supporting this endeavor as well, but we are in the midst of developing all cooperations within the European Reference Network in order to have these new treatments available for this particular group of patients with rare eye diseases.

Gene therapy registered in European Union is a big help for patients. Are there other new gene therapies coming for inherited retinal eye diseases?

I am sure that Lublin will be one of the centers  that will help developing new gene therapy developments together with consortia like the ERN and/or also together with companies  funding these expensive clinical trials.

 Do you expect  support to come from the  European Union and also national healthcare systems to support gene therapies and the application to patients?

That is of course the essential next step. Let us take the example of the one gene therapy  that  is already on the market. It is called Luxturna. It was initially developed in  the USA and a large company now distributes it in Europe. For each individual country, negotiations for reimbursement are necessary. Because  10 to 15 years of development have been necessary, these are very expensive treatments, although it takes only a single injection into the subretinal space of the eye to stop the disease. But the healthcare system in each country needs to be aware of this possibility to avoid blindness. Blindness is very expensive because blind people cannot  contribute  very much to the economy but  rather they need financial help. To stop blindness is a big saving for the country but first the healthcare system has to pay the treatments before this treatment can be effective. A lot of convincing arguments and  skillful, tenacious negotiation is necessary in each country to increase public awareness and to increase  the willingness of public health insurances to provide the funds to help. We have similar cases in many other medical conditions like Leukemia. Many forms of Leukemia can be treated nowadays and each Leukemia treatment costs hundreds of thousands of Euros. This is to say that there are treatments which are effective in an individual but they are very costly. On the other hand these are rare diseases, so there are not so many people in Poland who will need this therapy. This all needs to be negotiated with the healthcare system administrations and I hope that many countries, and especially Poland, will open these possibilities for the citizens.

Congratulations that your work and research is so successful to bring new ideas into the patient care to treat patients. Isn`t this the biggest satisfaction and prize for the researcher and doctor, when he/she can transfer ideas to the real treatment and help the patient?

That is true. It is a very rewarding experience and it is necessary to involve oneself deeply in basic science in order to get a feeling what will come alive and what might be feasible. Basic science is extremely important but it needs to be closely linked to clinical practice, as some of our knowledge derived from basic science will materialize only decades later; we need to foster and speed up this process  To find the ways that transfer knowledge to accessible therapies is a big difficulty and one has to invest  long years of study time and perseverance. Therefore it is very rewarding if it works. For instance in 1989, when we started to collect blood from patients with hereditary retinal diseases and looking for the gene defect, which was very difficult at that time, people asked: “Why are you doing this, there is no therapy, it does not matter which gene defect a person has, so why are you spending all the time and money?” Only few  clinical-scientists understood that it is only if we know the basic defect in the cellular system that we will have the possibility to repair or to prevent worsening. That needs basic science and I was a basic scientist for more than 10 years before I became  an ophthalmologist. It was clear that we had to invest efforts at an early time in order to be ready for this therapeutic development once the technology was available. So we started early; we now have more than 20.000 DNA probes from patients here in Tübingen in the refrigerators and we have investigated more than 10.000-11.000 patients with these diseases. Therefore we have cohorts for clinical trials and the companies or the investigators are coming to us because they know here in Tübingen we have the patients readily available that may benefit from treatments and who can join clinical trials quickly.  It is very rewarding and the biggest satisfaction for me as a scientist-clinician to see that ideas and concepts come alive over the years that help my patients, suffering men and women, whom I know personally and to see their joy or justified hope. Of course I am very happy to go on working. My University gave me a new professorship when I was formally retired so I did not give a farewell lecture but an inaugural lecture for the new professorship called “senior professorship”. Therefore I still have postdocs, doctoral students, secretary and visitors and I have the joy of going on and seeing that what we have started so early can now become a benefit to our patients.

 Thank you very much for the interview and congratulations for all efforts and time but also great success and great help for the patients!

In 2012 the Medical University of Lublin honored Prof. Eberhart Zrenner,s with an honorary doctorate title for his enormous contribution to the development of scientific research in the field of ophthalmology.

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