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A New Technique for Restoring Normal Vision to the Blind: The Technology of Prof. Sheila Nirenberg of Weill Cornell Medical Scho

Posted May 07 2013 1:26pm
About a year ago, a colleague put me in touch with a Boston-based venture capitalist who was interested in a new method for restoring vision to the blind that was under development at Cornell University. I did some cursory research about the technology and wrote a brief report about what I learned.

I really didn’t understand the front end of the technology – how the research team was able to acquire and manage a useful visual signal that could be converted into sight by the brain, but since the back end involved the use of gene therapy, which I was very interested in, I began a file to collect information about this technology.

Then, about a month ago, I learned that Dr. Sheila Nirenberg, the team leader, would be giving a presentation about her technology at an Optogenetics Conference that was being held in the Boston area. I contacted the symposium director and obtained an invitation to sit in on Dr. Nirenberg’s talk.
On May 1st, I went to the conference, met Dr. Nirenberg, listened to her presentation and literally got blown away!
I decided on the spot that I needed to learn more about what she and her team were doing and the best way was to write about it. So, I plunged in, did the research to learn more about what the Cornell team were doing, and with Dr. Nirenberg’s cooperation, here is my explanation of what I believe she and her team are doing and what her technology might be able to accomplish.
Introduction
Follow along with me for a minute. After a gene therapy injection (to place a light-activated dye into the ganglion cells of the retina) in a short procedure at a doctor’s office, a blind person suffering from retinitis pigmentosa, usher syndrome, or geographic atrophy (whose photoreceptors – the rods and cones – have been severely damaged) dons a unique pair of glasses (or goggles) and due to the magic of the Nirenberg conversion technology has his/her sight restored to something close to normal vision! That is what Dr. Nirenberg and her team is hoping to accomplish. She’s done it with animals so far and it raises exciting possibilities that it can be done with humans.
So, that raises these important questions: how does it work, how does it compare to other retinal prosthetic devices/methods being developed, and when will it become available for human clinical trials?
I will attempt to answer these questions.


How the Technology Works
In a normally-sighted person, the front of the eye focuses an image onto the retina. The image lands on the photoreceptors, which in turn sends the signals into the retinal circuitry, which processes them and converts them into a code. The code is in the form of  a series of electrical pulses, which get transmitted to the brain via the ganglion cells, which fine-tunes the visual information that is sent to the brain.

Fig. 1. The transformations of images into patterns of action potentials by the retina.

In a person with a retinal degenerative disease that destroys the photoreceptors, this train of events is short-circuited, and no light pulse information reaches the brain.  
What Dr. Nirenberg’s technology does is jump over the damaged tissue and contact the ganglion cells directly and drive them to send the code to the brain.       
The key to making this technology work, or the “eureka” moment, was when Dr. Nirenberg realized that what was needed was to provide a train of electrical pulses – the “code” – to the brain in a form that it was used to receiving and using to form an image or vision. In order to do this, she and her team came up with a two-fold approach, composed of an “encoder” to deliver the train of electrical pulses to the retinal structure that remained, and a “transducer” to recognize the “code” and transmit a similar pattern of electrical pulses to the visual cortex in the brain via the enhanced ganglion cells.
The encoder is composed of a pair of glasses or goggles that include a camera to capture what is being seen (think of the high-resolution camera in your iPhone or smartphone), a small programmable computer chip that converts the pixels seen by the camera into a coded pattern of electrical pulses that are “readable” or recognizable by the brain, and a mini-DLP (a mini-digital light projector) that transmits the light pulses to the retina (or that portion of the retina that contains the dye that can be activated by the light pulses).
I won’t get into how Dr. Nirenberg and her team came up with the algorithm that enables the procedure to work. That is aptly described in her paper (and the supporting information) recently published in Proceedings of the National Academy of Sciences (1).
The “transducer” portion, that enables the brain to “see” the train of light pulses, is composed of a light-sensitive dye (a protein – channelrhodopsin-2 or ChR2) that is injected into the eye, similar to the way Avastin is injected for treating the wet form of AMD, using a gene therapy technique called optogenetics, that places the dye into the ganglion cells of the retina.
As defined by Wikipedia, Optogenetics is a neuromodulation technique employed in behavioral neuroscience that uses a  combination of genetic and optical methods to control specific events in targeted cells of living tissue, even within freely moving mammals and other animals, with the temporal precision (millisecond-timescale) needed to keep pace with functioning intact biological systems.
In retinitis pigmentosa and other similar retinal diseases, the photoreceptors are destroyed, but the ganglion cells, which are part of the retinal system that are attached to the photoreceptors, usually are not, which is what makes them a prime target for vision restoration. By employing gene therapy to “carry” the light sensitive dye into the ganglion cells, the mini-DLP of the encoder fires the coded light pulses into individual ganglion cells, which in turn causes the light sensitive ChR2 dye to, in turn, fire light pulses which are carried by neurons via the visual cortex into the brain, which can recognize the code and turn it into vision.
In this way, what the camera in the glasses detect, is sent (in the proper form) to the brain which recognizes the signal and allows a blinded person to “see”.

Fig. 2. Images reconstructed from the blind retinas treated with the prosthetic. A. Original image. B. Left, image reconstructed from the firing patterns of the encoder. Right, image reconstructed from the firing patterns of the blind retina viewing the image through the encoder-ChR2 prosthetic. C. Image reconstructed from the firing patterns of the blind retina viewing the image through the standard optogenetic prosthetic (just ChR2, no encoder).



Competing Technologies – Retinal Prostheses, Stem Cells, Gene Therapy and Others Working with Optogenetics
As a means of putting Dr. Nirenberg’s technology into perspective, as one of the many approaches that are being developed for the ophthalmologist’s armamentarium for treating RP,  dry AMD, and other retinal degenerative disesases, I include the following information about the state of research for other experimental techniques/therapies that may find use in treating these diseases.
Retinal Prostheses (2)
In those with retinitis pigmentosa (RP) and similar retinal diseases, the retinal degeneration affects the retinal pigment epithelium and the photoreceptors. Eyes with RP respond to electrical stimulation because in many patients, the inner retina, particularly the ganglion cell layer, still has some function. The retinal chip implants stimulate these cells.
More than a dozen groups of investigators and companies around the world are working on retinal implants. In order to restore visual function, chip implants have to detect light, convert the light energy to electrical energy, and then stimulate the retina. Different groups approach this in different ways. Two of the implants that are furthest along the path to clinical availability are the Argus II Implant by Second Sight (now FDA approved), and the Active Subretinal Implant by Retinal Implant AG. The Argus Implant directly stimulates the ganglion cells. The Active Subretinal Implant recreates some of the signals that normally would have been made by the photoreceptors.
The Argus II Implant consists of four parts. The power comes from a battery pack worn on the hip. An external video camera wirelessly delivers images to the electrical housing that is affixed to the episclera. The image and data processing are done here. A cable from the electrical housing enters the eye through an incision in the pars plana and the electrical impulses then are sent through the cable to the chip. The chip itself is attached to the retina with a tack.
In clinical testing of the Second Sight implant, all 30 patients who received the implant during the trial were able to perceive light during stimulation. More than half of the patients were able to see the motion of a white bar moving across a black background. Many of the implanted patients were able to identify some 3 to 4.5 cm letters on a high-contrast background. The best vision to date was 20/1,262.
The Active Subretinal Implant is currently in clinical trials in several European centers and in Asia. This implant contains a 1,500-electrode array that directly stimulates the inner retina. In contrast to the Argus II implant, which bypasses the inner retina, the Active Subretinal Implant aims to replace the dysfunctional photoreceptors.
The Active Subretinal Implant contains photodiodes on the subretinal chip, so there is no camera. The light stimulation occurs similar to the way we see-the light coming from an object goes through the pupil and activates the implant, which then converts the light directly into electrical stimulation. In contrast to the epiretinal implant, the subretinal implant does the image processing within the chip itself. However, using this technology requires more energy than light can provide. This is provided via a handheld battery pack that also has controls for brightness and contrast. The necessary energy is transmitted transdermally via a receiver induction coil and a magnet that is implanted under the skin behind the ear. A subdermal cable tacked to the lateral canthus connects the receiver to the subretinal implant for energy.
There are published reports on a total of 21 patients who have received the subretinal 1,500-photodiode implant. Those patients have achieved VA of up to 20/1,000 within an 11 degree by 11 degree visual field. Functional outcomes included localization of objects of daily life such as plates and drinking glasses; increased mobility; motion detection; orientation in outside environments; recognition of facial details; even reading and detecting spelling errors in words written in letters 6-8 cm in size.
The basic take-away from a review of the work being done with direct retinal implants is that they are limited by the number of photodiodes that can be implanted – and by the direct light pulse information that can be transferred to the implant. The key, as I see it, is that Dr. Nirenberg has invented a “better” way to input a visual signal and unless that is incorporated into the retinal implant systems (as she has proposed to with Second Sight), they will never approach the conversion rate that she claims to have achieved.
Stem Cells, Cell (Drug) Therapy, and Laser Treatment
As I have previously written (3), a number of companies/institutions are using both adult and embryonic stem cells to invigorate the retinal epithelial layer that feeds the photoreceptors, in the hope of regenerating some activity in the photoreceptors. One company, Neurotech, is using encapsulated human RPE cells to secrete ciliary neurotrophic factor CNTF), which they believe is capable of rescuing and protecting dying photoreceptor cells.
Meanwhile, Ellex Laser has a research program aimed at “retinal regeneration” by using its laser to stimulate the RPE cells to release enzymes that are capable of “cleansing” Bruch’s membrane in the hope of rejuvinating the retina (photoreceptors) by allowing the increased transport of water and chemicals across this important membrance. (This technique might have some bearing in macular edema and in the early stages of dry AMD in drusen reduction, but I don’t see how it would affect the photorecptors (4).)
Gene Therapy and Optogenetics
As is clearly pointed out in my table on the use of gene therapy in ophthalmology (5), a number of companies and institutions are in the pre-clinical and clinical stages of developing gene therapy approaches for the treatment of dry AMD (geographic atrophy), RP and Usher’s Syndrome. Hemera and Oxford BioMedica are taking straight gene therapy approaches, while a number of companies/institutions are involved in using optogenetic gene therapy. Among those using optogenetics that I am aware of, are EOS Neuroscience, GenSight Biologics, RetroSense, the University of California at Berkeley, and the Instituite de la Vision (Paris).
Of course, it should be mentioned that Dr. Nirenberg is working with Dr. William Hauswirth of the University of Florida, in her pursuit of an optogentic approach to solving the problem of restoring vision for the blind.
Again, as I noted in the conclusion to the section on retinal implants, my belief is that none of these techniques (except of course for the work of Dr. Nirenberg and Hauswirth) should accomplish as good results without the inventive front end visual signal supplied by Dr. Nirenberg’s work. Input equals output and the best input should provide the best output!
Status of the Invention
As reported to me by Dr. Nirenberg, the original work done with mice has now led to work with primates. Her lab has constructed a device for use with the primates and, in conjunction with Dr. Hauswirth, they are now testing an array of channelrhodopsin-expressing vectors to be able to select the best candidates for a Phase I/II human clinical trial. As she states (6), “For a vector to serve this purpose, it has to a) produce normal firing patterns in blind retinas (as has been done in the mouse), and b) produce normal firing patterns in the specific cell classes we target, which are ganglion cells or subclasses of ganglion cells.”
“We are currently working with 8 AAV-2 vectors; they vary in the channelrhodopsin used, in the promoter to drive expression, and in the enhancer components. So far, at least 2 of the vectors satisfy these conditions, that is, they express channelrohodopsin in primate ganglion cells in vivo, and they express it strongly enough to allow normal firing patterns to be produced when they’re stimulated by the device. The next steps are to modify the vectors for humans and to perform safety studies (typically, studies in two species are recquired), and then (to) prepare a package for FDA for evaluation.”
“Thus, although it is likely that there will be hurdles to overcome to bring this technology to patients, the major ones – a vector (AAV) for delivering channelrhodopsin to ganglion cells, and encoder/stimulator device to drive them, and the fact that targeting a single ganglion cells class by itself can bring substantial vision restoration – have already been addressed, substantially increasing the probability of success.”

In conclusion, I should note that with all of the previous work done in the 16 gene therapy in ophthalmology clinical trials either currently underway or completed, the time to get into a clinical trial with the specific gene therapy vector chosen, should be short, rather than long. And then, the real test to demonstrate the ability of the Nirenberg Technique to restore vision to the blind, will begin.

Note: To view a presentation similar to the one I sat in on on May 1st,  please take a look at Dr. Nirenberg’s presentation at TED MED 2011 in October 2011.

Footnotes:
1. Retinal prosthetic strategy with the capacity to restore normal vision , Sheila Nirenberg and Chethan Pandarinath, PNAS, August 2012; Supporting Information , same source.
2. Retinal Prostheses Offer Hope to Blind Patients , Sunir Garg, MD, Review of Ophthalmology, March 15, 2013
3. A Primer on the Use of Stem Cells in Ophthalmology , Irv Arons’ Journal, Sept. 2010
4. Ellex 2RT Retinal Regneration Laser: An Update – First Clinical Results , Irv Arons’ Journal, April 19, 2010.
5. Table 2. Gene Therapy in Ophthalmology by Application , Irv Arons, latest update.
6. Research Interests , Sheila Nirenberg, March 13, 2013.


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