Friday, May 17, 2013

Stem Cells in Ophthalmology Update 25: ACT Patient in Dry AMD Trial Goes from 20/400 to 20/40!

The story started innocently enough. On Wednesday, May 15th, the journal Cell reported on a study that claimed biologists had finally created human stem cells by the same technique that produced Dolly the cloned sheep in 1996. They transplanted genetic material from an adult cell into an egg whose own DNA had been removed.

OK, an important story but what followed boggles the mind. Many science reporters wrote about the discovery which got picked up by several news sources. However, a sharp-eyed member of the Investor Stemcell Forum (iCell), a group originally started by investors in Advanced Cell Technology, noticed a quote at the end of Sharon Begley’s writeup. Sharon is a science reporter writing for Reuters. She had obtained quotes from several people working in the stem cell field, including at the very end of her story, the following quote from Dr. Robert Lanza, the Chief Scientific Officer of Advanced Cell Technology (ACT), “The most promising human study is ACT's. It is two years into clinical trials using stem cells derived from human embryos to treat two forms of blindness, including macular degeneration, with encouraging results. One patient's vision went from 20/400 to 20/40, said Lanza.

By Wednesday afternoon and into the evening, the iCell bulletin board went wild. There are more than 3000 members of this board and most are investors in ACT (or one of the other many stem cell companies discussed). Editor’s note: I am not a shareholder/investor, along with a few others, like Paul Knoepfler of Univ. of Cal. Davis, who are invited members because we write about the field. In the evening when I entered the board, there were several hundred comments all speculating whether the quote was accurate or, somehow, a mis-quote. This was the first time any of us had heard that a patient had achieved that level of correction.

Apparently, the SEC also took notice, because the next morning (Thursday, May 16th), the company was forced to acknowledge that the quote was accurate. In its statement, the company said, “Advanced Cell Technology today confirmed that the vision of a patient enrolled in a clinical investigation of the company's retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) has improved from 20/400 to 20/40 following treatment. The improvement was first reported on May 15, 2013, in a news article published by Reuters.”

"We continue to be encouraged by the progress we see in our ongoing clinical investigations, though the results included in the article were confidential and not intended for publication at that time," commented Gary Rabin, chairman and CEO of ACT. "Our plan is still to publish additional results from the clinical investigations when we have a significant aggregation of data."

Now we knew that a patient in one of the company’s clinical trials (there are three of them – two for treating Stargardt’s Disease – one in the U.S. and the other in the UK; and one for the dry form of AMD in the U.S.) had achieved unparalleled improvement. So, which clinical trial?

I speculated that it was probably in the dry AMD trial, because in the SMD trials, the patients treated had quite damaged photoreceptors which I didn’t believe could recover to that degree, but confirmation was still needed.

That evening, I asked the iCell board if anyone had confirmed which clinical trial had produced the significant results – and I got a private message providing the answer. I was right, it was a patient in the dry AMD clinical trial.

So, what is the significance of this development. It is significant because it shows that, for the first time, a person suffering with the dry form of AMD (90% of all those with AMD) can obtain improved vision, going from legally blind (20/400), to normal vision (20/40), good enough to obtain a driver’s license in most states. Yes, this is just one patient, and early in this clinical trial, but hope prevails. If this much improvement can be obtained with one patient, and that patient with very poor vision, than think what can be obtained starting with people with much less a degree of poor vision, 20/100, for example, which is part 2a of the Phase II clinical trial.

I am hopeful that ACT is on the right track.

Tuesday, May 07, 2013

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

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.


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.


Because of all the publicity this writeup has received, many of you may think that this procedure is "right around the corner". That is not so. Dr. Nirenberg has just done this in blind animals and is developing it now for humans. She still has to pass through the FDA, do safety studies, etc., before the first clinical trials can begin.  So, please be patient.

Update - August 2014

In mid-August, I contacted Dr. Nirenberg to ask about progress being made with the new technique and she kindly sent back the following response:

“We have made a new device that can be used in the future human clinical trial, and we're currently setting up safety studies with it on rodents and primates.”

“We've teamed up with Sam Jacobson's group at University of Pennsylvania to do the trial, so we had to build a device that works with their equipment. By integrating with their equipment, we can better stimulate and monitor the patient's retina. We're very happy to be working with them, since they have extensive experience in gene therapy, working with the FDA, and setting up clinical trials, and they're compulsive and worry a lot like we do.”


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

6. Research Interests, Sheila Nirenberg, March 13, 2013.