00:00:09:19 - 00:00:35:11 José-Alain Sahel Breaking the rules to restoring vision for retinal degeneration, how the use of optogenetics can restore vision to the visually impaired Jose Allan Salle, University of Pittsburgh School of Medicine, Institute de la Vision, Sorbonne University on November 9th. 1989. I was at my home in Strasburg and kept thinking of the significance of the event for the future. 00:00:46:22 - 00:01:11:03 José-Alain Sahel Well, thank you very much. Difficult to follow you, so I'll try to be the disappointing if. Well. It's a big honor for me to be here today, and I didn't realize the impact it would have on me remembering many things. So you mentioned also. Totally. Totally was an ophthalmologist and he passed away after telling about this virus almost two years ago. 00:01:12:01 - 00:01:33:09 José-Alain Sahel We work I'm going to present to you the work of many people, and especially I want to mention. But on Rosekind Basil, we have been working together on that for 15 years. And you've worked fruitcakes for me, 15, 20, 15 and 25 years. And my collaborator Surgical and an Carol, but also many other people that have been part of us, including industry. 00:01:35:03 - 00:02:02:03 José-Alain Sahel Almost two centuries ago, two centuries. 250 years ago, the French philosopher the needed role wrote a letter that brought him to jail, actually to serve in jail. It was written in the blind and he was trying to discuss this concept of regaining vision and also what we can learn from the blind. He was referring to this idea that we believe the truth is something we can touch on, something we can see. 00:02:02:15 - 00:02:29:15 José-Alain Sahel For the blind, they have to touch for us. We have to see. And we believe that what we see is the truth. The question that was raised in his letter was a question that was actually addressed to the philosopher John Locke a few years before by a neurophysiologist called Modena. The question would be, in case someone who has been blind and was able to recognize the shapes by touching them is regaining vision. 00:02:30:00 - 00:02:53:03 José-Alain Sahel Does he have to learn how to see, or is this vision to be made to be automatically transmitted to the brain just through the eyes recognizes? Because I know you think this for you. This is a cube, for example. Is this a possibility? This question has been at the core of many philosophical discussions for 200 years and more and is still unsolved. 00:02:53:03 - 00:03:19:03 José-Alain Sahel But as scientists working on vision restoration, we are confronted to. And I want to tell you about the journey of a patient and the journey of scientists and technologies trying to address this specific question. The question is the question that was really impacting this person. This man was infected with a disease called retinitis pigmentosa. It's the most frequent genetic disease that leads to blindness. 00:03:19:12 - 00:03:43:01 José-Alain Sahel And he heard about it when he was a teenager. And eventually, over the course of almost 40 years, he lost totally vision and had been blind for 50 years. So he will speak a couple of times during this speech. So the solution is not there. Now, the emotions come in visually. You have to the sentiment you make with the chief vitality utility, the Seabiscuit. 00:03:43:01 - 00:04:24:17 José-Alain Sahel You get to two different agencies will let you tell Nichols. So this person had been blind for 15 years. When you entered this clinical trial, this clinical trial was really trying to address the need for him to restore some level of vision and it using a technology that is really trying to I hope the movie will play to replace the photoreceptors when we see the light is entering the eye of a pupil and is reaching the photoreceptors at the deaf of a retina but absorbing light, convert that into electrical signal that is processed in the retina as a normal tissue and gets transmitted through the optic nerve to the brain. 00:04:25:01 - 00:04:45:12 José-Alain Sahel And the brain is the place where we see the images are formed and really not processed into the brain. In retinitis pigmentosa, the photoreceptors are dying. And because we are dying there is no ability to capture the light and no ability to transform the light into electrical signal, which means that there is no information to give to the brain. 00:04:45:18 - 00:05:07:23 José-Alain Sahel And this is blindness. So the question is how can we replace photoreceptors? There are many approaches to that, but the one I'm going to talk today is called Optogenetic Optogenetic was actually to rediscover Earth almost more than 50 years ago by a German scientist. Her name to be taken only was here yesterday for the science meeting at the charity Symposium. 00:05:08:18 - 00:05:33:17 José-Alain Sahel Hence, Malmberg draws Nagel and Roosevelt, and it's something that does exist in algae. This is a typical discovery in science, but nobody thinks it's useful in anything. Algae are getting towards the light because they are hovering at the surface of specific protein that carries both a channel and a chromosome, which means they can absorb the light and convert the light into a signal. 00:05:33:23 - 00:05:59:03 José-Alain Sahel And this is prompting the algae to get toward the light proof tragically, this mechanism is in one protein recapitulating. What we have in the human retina, in mammalian retina, where hundreds of proteins are absorbing the light, transforming the signal into into electrical signal that is amplified by 1 million. So why do we need something so complex is because we need to adapt to many levels of life. 00:05:59:08 - 00:06:21:03 José-Alain Sahel And because we have much higher resolution than algae. But anyway, this specific protein could be used to stimulate neurons or any cells. And the idea came obviously too many people to use that in neuroscience. And this is what's happened. For example, we've called the short end at Boyden, but a few people like us it but maybe this could be a ploy to restore vision by replacing photoreceptors. 00:06:21:23 - 00:06:44:21 José-Alain Sahel So our goal was to transfer it to using gene therapy remaining cells in the retina. And we tried all the cell types. So we have been working on in parallel to all these approaches. But when I'm going to mention today, he's targeting the cells that are remaining in even advanced stages of retinitis pigmentosa, other ganglion cells, the cells that are forming the optic nerve. 00:06:45:07 - 00:07:09:11 José-Alain Sahel So for many steps, we worked on how to deliver the gene to the retina and what protein to use. And we ended up with this combination therapy that is a combination of a vector that carries the gene coding from a protein for this very specific optogenetic protein that is expressed in the guidance cells and coupled with a medical device that I will discuss in a moment. 00:07:10:16 - 00:07:29:09 José-Alain Sahel We have to find the light that is necessary. The initial proteins that we have discovered by the scientist need a huge amount of light to be activated. And this amount of sight would be impossible to use in humans because it would be toxic to the retina. So we have to find a way to shift that into something which would be safe. 00:07:29:19 - 00:07:52:01 José-Alain Sahel And we tried many of them and eventually identified one called proofs A that was developed. They might be avoided, but was really seeking what we needed being shifted into Viread, which is far less infiltrating and needing an amount of light, which is perfectly safe. So we tested virtually in many animal models and eventually move that to the clinical trial. 00:07:52:01 - 00:08:20:04 José-Alain Sahel So how does it work The protein is expressed to deliver liver ganglion cells and the ambient light doesn't work, doesn't trigger anything. But if you use a very highly activated amount of light, then you are able to activate these proteins and these proteins are eliciting a signal and this signal is resulting from the fact that the goggles that I will show you in a moment are really able to stimulate the retina with enough levels of light. 00:08:20:13 - 00:08:48:22 José-Alain Sahel So these goggles have a camera in front of them, and these cameras are well described to you and they are sending you information. And then the brain has to learn how to see because this type of information is not a natural type of information. So the therapy we developed is a combination of a gene therapy and a medical device to be able to activate that So we have to learn how the retinal C's, the retina is speaking a very specific language. 00:08:49:05 - 00:09:13:14 José-Alain Sahel And for example, we free chips. This is, for example, this fear that, you know, is asking about. This is the cube. And each of them has a specific signature. So how does it work? The retina is detecting any change at the nanosecond, and any change is really microsecond. And any change is really eliciting a specific signal because of this approach, which is more or less even based. 00:09:13:14 - 00:09:33:02 José-Alain Sahel Any change is eliciting a signal. We try to use a system that would mimic that. And so that we use a type of camera that was over the front of the goggles that the patient is using. And the voice processing leads to a signal that is emitted at the back of the goggles towards the eye. So I will show you how these cameras work. 00:09:33:02 - 00:09:55:03 José-Alain Sahel Hopefully it will work naturally well. So if you want to turn down the light and we will see this camera. So this camera is detecting me when I am moving. If I am not moving off this field, I'm going to disappear if I'm moving again. This is creating a signal. And this signal is the one that the retina is using. 00:09:55:16 - 00:10:18:00 José-Alain Sahel Interestingly, when we take pictures and you can bring back the light if you want, when we take pictures, you can bring back the light if you want. We are using a lot of information that is useless because nothing is moving except a small part of the scenery we are looking at. So the goal is to send to the eye only the information that is useful, namely the change. 00:10:18:00 - 00:10:38:05 José-Alain Sahel And this is what these cameras are doing. There are specific recordings of the change. They send a light, which is in the amber spectrum that corresponds to the absorption by the retina. So how does it work for the patient? The signal is then transmitted to the brain, and then there is a long process that took several months for the patient to learn how to interpret these images. 00:10:38:13 - 00:11:01:07 José-Alain Sahel It's partial restoration and I'll show you in real time what's happened with the patient virtually straying from that. And this is what this movie is going to show you. If it plays Sorry, I have to go back. So can you play the movie? Oh, oh. Maybe it's going to play, hopefully some kind of similarly calm and genuine voice. 00:11:01:07 - 00:11:24:14 José-Alain Sahel Bond, was it involved? Competition. Not that one. The one on the side. Sorry. So, okay. Uh, so normally you would see the patient who doesn't want one? No, no. We so. So can you back then you go back to the. Okay, we know it's really not doing well. Okay. So this movie should play if you can have it play. 00:11:26:04 - 00:11:54:14 José-Alain Sahel Okay. Okay, so this is without the goggles. And the patient is trying to screen so it doesn't. Yes, but the injured people, these are not have goggles. So he's trying to screen the table to find the voice on the object. No, no. And doesn't see anything. No evil goggles. And he is now scanning again the table and on this computer, this is what the camera is projecting onto the eye and the patient is scanning that. 00:11:54:14 - 00:12:30:17 José-Alain Sahel So it's it's a real time activity. And so at some point you will be able to align. No, we will improve. Okay. So is detecting something which is key to know cinema and or is concerned to do something wonderful in this place to show gravity can work. Does it help? Long as you know, we keep telling you okay. 00:12:30:17 - 00:12:49:13 José-Alain Sahel So is detecting that. So what does it mean for the patient? He is now able to count objects. He's able to see the stripes of him across the street. And I'm going to report at the end of the week as the American Academy on observations in this trial. So going back to the whole discussion we have to see. 00:12:49:22 - 00:13:06:00 José-Alain Sahel But when we see actually we are learning how to see as kids, but we don't know about it. And the blind have to learn how to make sense of what they see. And really they have to confront the inner vision they had before, which was really through touch to the vision. We are getting back through this new perception. 00:13:06:12 - 00:13:26:04 José-Alain Sahel Many years ago, Michael Schumacher, talking about the birth of a clinic, was mentioning that we tend to equate the truth and the vision, but the truth is something that needs naivete of gays, something which is totally new. And this is the type of new vision that people are regaining. But this equation between the truth and the vision is something we use every day. 00:13:26:04 - 00:13:49:17 José-Alain Sahel In every life. And we tend to believe that vision is everything is very important. And it's a it's a major thing, actually. When did who spoke about that about the truth and about the impairment he was brought to chair. And this is a connection, I think, to what we are seeing today. There are many voices, many aspects of truth many visions that are very different, many types of niceties. 00:13:49:22 - 00:14:12:24 José-Alain Sahel And this is for me, what we call a society. And at some point there is a need for the vision of both sides to come across to each other. And the important aspect of every research we do is to try to restore some level of vision, which is more or less transforming blind patients into visually impaired patient. But visually impaired patients are still facing a society that is not prepared to take care of them. 00:14:13:09 - 00:14:36:16 José-Alain Sahel And so we have to learn these words the society has to be inclusive enough so that people that are either blind or visually impaired on any type of impairment can have an easier journey towards autonomy and not just thinking of them as handicapped people, but to autonomous people. And we need to really pair what is scientific innovation we societal transformation. 00:14:36:22 - 00:15:01:02 José-Alain Sahel And this is still a lot of work we have to do. This event is an amazing event because it probably gives some clues about how we have in the dialog in society, which helps us to bring more to our patient. I'll give the last word to our patient of the book in terms of more of if you say if you do see commitments, we can see extraordinary on the wrong side of what? 00:15:01:02 - 00:15:05:13 José-Alain Sahel I don't know what else to do on this. Well, thank you very much.