Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies

Researchers at the University of California at Berkeley, along with some assistance from the Flaum Eye Institute and Center for Visual Science at the University of Rochester, have come up with a new version of an adeno-associated virus (AAV) vector that can deliver genes deep into the retina using an intravitreal injection of the vector into the vitreous, a less-invasive technique, instead of an intraretinal injection below the surface of the retina, which is the usual way gene therapy is currently delivered.

The study was authored by postdoctoral fellows Deniz Dalkaral (then with Helen Wills Neuroscience Institute of UCal Berkeley, but now with Institut de la Vision in Paris) and Leah C. Byrne (Helen Wills), and graduate students Ryan R. Klimczak and Meike Visel (UCal Berkeley’s Dept. of Molecular and Cell Biology), and Lu Yin and William H. Merigan (Flaum Eye Institute and Center for Visual Science at the Univ. of Rochester), under the direction of Professors John G. Flannery, and David V. Schaffer of UCal Berkeley. The paper, “In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous”, was published online on June 12th in Science Tranlational Medicine.

As explained by Dr. Jean Bennett, a professor of ophthalmology at the University of Pennsylvania in Philadelphia, who was not involved in the study, but who has done extensive work with gene therapy in the treatment of Leber’s congenital amaurosis, “It shows the results of a very clever system to evolve AAV to target cells in the retina efficiently from an intravitreal injection.”

“Intravitreal injection, whereby a needle is pushed into the eye’s vitreous, or gel-like core, is a common drug delivery procedure performed under local anesthetic in a doctor’s office”, explained Bennett. “But using this routine injection technique in trials of gene therapy for retinal degeneration has thus far proven impossible.”

The problem, as explained by Dr. David Schaffer, a professor of chemical and biomolecular engineering, bioengineering, and neuroscience at the University of California, Berkeley, who led the research, is that current AAV vectors are incapable of penetrating deep into the retina where the target cells for retinal diseases are located. “AAV is a respiratory virus and so it evolved to infect lung epithelial cells,” explained Schaffer, “It never evolved to penetrate deep into tissue.”

Patients receiving gene therapy have theretofore undergone a vitrectomy (removal of the vitreous) and a direct intraretinal injection, which requires hospitalization and general anesthetic, and can sometimes even damage the retina. “If it were possible to inject AAV into the vitreous instead of the retina and still get gene delivery to the target cells, said Bennett, “one could envision the [doctor saying], ‘Ok, well just come into the office and get your gene therapy, tomorrow afternoon at two.’”

With that aim, Schaffer and colleagues used a process called “directed evolution” to randomly create millions of variations of the AAV virus to determine which ones were better at tissue penetration. They injected regular AAV into the vitreous of mouse eyes and one week later collected photoreceptor cells from deep within the retina. The tiny percentage of AAV vectors that made it into those cells were then amplified, repackaged into virus particles and injected into the vitreous again. They repeated the injection, recovery, and amplification a total of six times, finally isolating 48 AAV variants for sequencing. Two thirds of those isolates turned out to be the same variant, and Schaffer and colleagues named it 7m8.

Lastly, to determine whether the 7m8 vector would be likely to show similar deep penetration in the human retina, Schaffer had the vector carrying a gene-encoding fluorescent protein injected into the vitreous of macaque eyes. Primate retinas are considerably thicker than those of mice, and the vector did not consistently reach the deep cell layers – showing a spotty penetration pattern rather than the wide and even pan-retinal penetration that had been seen in the mice. However, 7m8 did effectively target photoreceptor cells of the fovea – a thinner part of the primate retina that is essential for the sharp detailed vision humans use when reading and driving. “That’s a really important region to protect,” said Schaffer. “For the quality of life of patients who are going blind, if you can at least protect the fovea that would be a huge improvement.”

Eye cells labeled with green fluorescent protein have successfully taken up the virus, showing that the ‘evolved’ virus (right) is more effective than the virus currently used for gene therapy (left). The new virus is particularly good at targeting the critical photoreceptors (top layer). (Source: University of California, Berkeley)

Note: All of the “directed evolution” work with mice to discover the 7m8 AAV vector was done at UCal Berkeley, while the confirmatory primate injection and imaging was done at the Univ. of Rochester.

Schaffer and colleagues don’t yet know what makes the 7m8 vector so much better at tissue penetration than its AAV ancestor, but they plan to find out and use that knowledge to further improve its penetration in the primate retina.

"Building upon 14 years of research, we have now created a virus that you just inject into the liquid vitreous humor inside the eye, and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically non-invasive and safe. "It's a 15-minute procedure, and you can likely go home that day."

The engineered virus works far better than current therapies when administered from the vitreous of the eye in rodent models of two human degenerative eye diseases (X-linked retinoschisis and Leber’s), and can penetrate photoreceptor cells in monkeys' eyes, which are similar to those of humans.

Schaffer said he and his team are now collaborating with other investigators to identify the patients most likely to benefit from this gene delivery technique and, after some preclinical development, hope soon to head into clinical trials.

Schaffer predicts that the viruses can be used not only to insert genes that restore function to non-working genes, but can knock out genes or halt processes that are actively killing retinal cells, which may be the case in age-related macular degeneration.

As noted by  Dr. Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness, one of the co-funders of the research, “This is a critical next step in the development of retinal gene therapies. The enhanced AAV holds potential for treating more of the retina and doing so more safely. Incremental advancements like this are essential to getting the best treatments out to the patients.”

The investigators showed efficacy for the 7m8 AAV in a large animal as well as mouse models of retinoschisis and Leber congenital amaurosis, or LCA (RPE65 mutations). In the mouse studies, the virus was able to penetrate the retina and deliver a corrective gene to enable the retina to function normally.

While the large animal did not have a retinal disease, the virus transduced many regions of its retina. Ultimately, in both types of animals, the AAV was able to deliver genetic cargo to a variety of retinal cells, including: photoreceptors, the cells that provide vision; the retinal pigment epithelium, a layer of cells providing nutrients and waste disposal; and ganglion cells, which are a target for emerging, vision-restoring optogenetic therapies. (Editor’s Note: See, for example, my writeup of the “Nirenberg Technique”, an optogenetic approach to restore near normal vision to the blind.)

Most notably, the intravitreally administered AAV was able to penetrate the fovea, a small pit in the center of the retina rich in cones, which provides the vision most critical to daily living, but is often made fragile by degenerative diseases. Researchers have been concerned that injections underneath the fovea could cause permanent damage and vision loss in patients with advanced degeneration in their central retina.

AAVs are currently used for gene delivery in several retinal gene therapy clinical trials, including those that have restored vision in children and young adults with LCA (RPE65). AAVs are attractive for gene delivery because of their natural ability to penetrate a variety of cells. In addition, humans are exposed to the virus in nature and, therefore, tolerate it well.

To identify the optimal AAV for intravitreal gene delivery, the scientists used a process called “directed evolution” to randomly create millions of variations of the virus. The variants were then screened in mice to identify the top candidates for gene delivery to the retina. In addition to looking for an AAV that could penetrate retinal cells well, the researchers searched for a variant that could pass through a formidable barrier in the eye known as the inner limiting membrane, or ILM, which separates the vitreous from the retina.

The scientists from UC Berkeley plan to work with others to perform additional toxicology and efficacy studies to ready the 7m8 AAV for study in humans.

Sources:

In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous, Deniz Dalkara1 et al, Science Translational Medicine, June 12, 2013

Genes Get in Your Eye: Directed evolution of a gene therapy virus vector improves its penetration into the retina, Ruth Williams, The Scientist, June 12, 2013

Easy and Effective Therapy to Restore Sight: Engineered Virus Will Improve Gene Therapy for Blinding Eye Diseases, Robert Sanders, University of California - Berkeley, June 12, 2013

Researchers Identify Better Virus for Retinal Gene Delivery, Foundation Fighting Blindness, June 12, 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.

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.

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.

Addendum:

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.

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.

Recently Published Articles: Current Status of Stem Cells and Gene Therapy in Ophthalmology

In the past couple of months, I was asked to update an article I wrote on stem cells in ophthalmology, originally published in Retina Today, for its sister publication, Advanced Ocular Care, and to write a similar article about the current status of gene therapy for another ophthalmic publication, Retinal Physician. These two articles have now been published in the respective journals and made available online.

Here is a brief summary of each article, along with the link to its online version and a note about finding the current versions of the tables associated with each, online.

The Current Status of Stem Cells in Eye Care, Advanced Ocular Care, March 2013

As noted, this is an update of the original article that appeared in the May/June issue of Retina Today.

“From an inauspicious start several years ago, the use of stem cells in the treatment of several ocular and retinal diseases has picked up steam over the past year.”

The article goes on to describe what stem cells are, the applications of stem cells in the various parts of the eye, a brief discussion of the status of some of the clinical trials, and concludes with a quote from Dr. Stephen Rose, chief research officer of the Foundation Fighting Blindness, who wrote, “Of course, it would be nice if all parts of our bodies, including our retinas, came with extended warranties so you could just swap them out when they go bad. But now that I think about it, that’s what stem cells might do for us someday.”

The Current Status of the Use of Gene Therapy in Ophthalmology, Retinal Physician, April 2013

“With the first approval of a gene therapy treatment for treating a genetic disorder in the Western world, the future of gene therapy for treating ocular disorders looks bright.”

The article goes on to discuss what gene therapy is and how it works; the applications of gene therapy in ophthalmology and clinical trial status for four ocular diseases – Leber’s Congenital Amaurosis, wet AMD, Stargardt Disease, and Usher Syndrom 1b; attempts to answer some remaining questions; and concludes with a quote from officials with the Office of Cellular, Tissue and Gene Therapies (OCTGT) for the FDA, “The recent history of gene therapy has been a mixture of promise and disappointment ... Despite the setbacks of the past, the OCTGT shares the enthusiasm of the field and is confident that ongoing clinical investigations will lead to commercially available gene therapy products that are safe and effective and advance the public health.”

Current Versions of Stem Cells and Gene Therapy Tables

Because of the lag between submission and publication of the above articles, the tables that are linked to the print and online versions of the above articles are currently out-of-date. I constantly update their contents and publish the latest versions online, which are accessible from my blog entry about each set of tables:

Stem Cells in Ophthalmology Update 24: Current Tables Now Online

Stem Cell/Cell Therapy Companies/Institutions Active in Ophthalmology

A list of thirty-two companies and institutions working with stem cells/cell therapies for ophthalmic applications. The table lists collaborators, the cell type being used, and the applications for which the cells will be used.

Link: http://tinyurl.com/StemCellComp

Stem Cell/Cell Therapy in Ophthalmology by Application

A list of sixteen ophthalmic applications being studied in clinical trials. The table includes the companies/institutions involved, the clinical trial status, and an active link for the clinical trial for those listed. (Thirty-six active and completed clinical trials are shown.)

Link: http://tinyurl.com/StemCellAppl

Stem Cell/Cell Therapy in Ophthalmology -- Ongoing & Completed Clinical Trial Details

A list of the the sixteen ophthalmic applications and the thirty-six clinical trials showing the number of patients to be studied in each trial and the number studied to date (that I am aware of). Active links are provided for each ongoing or completed trial.

Link: http://tinyurl.com/StemCellClncl423

Gene Therapy in Ophthalmology Update 16: Current Tables Now Online

Gene Therapy Companies/Institutions Active in Ophthalmology

The table lists more than thirty-two companies and institutions actively pursuing gene therapy solutions to ophthalmic diseases. The table shows the delivery viral platform, the gene type being used (where known), the application, and clinical status.

Link: http://tinyurl.com/GeneTherapyComp422

Gene Therapy in Ophthalmology by Application

This table, like the one for stem cells, lists the nineteen ophthalmic indications, the company/institutions involved, the clinical status, and the clinical trial number. (Sixteen active clinical trials are listed, with live links.)

Link: http://tinyurl.com/GeneTherapyAppl

Gene Therapy in Ophthalmology -- Ongoing Clinical Trial Details

Again, as with the stem cell clinical trial table, this table lists the sixteen active and completed clinical trials, the number of patients to be treated and the number of patients treated to date.

Link: http://tinyurl.com/GeneTherapyClncal

Note: The links in the tables associated with the clinical trials are “active” or “live” and will take you to each clinical trial on CinicalTrials.gov

A Personal Journey: How I Went From Being A Bench Chemist to An Expert Resource in Ophthalmology and Medical Lasers

A short while ago, I was asked by Maureen Duffy, editor of VisionAware, the blog of the American Foundation for the Blind, how I became so knowledgeable about ophthalmology and why I started my blog. I prepared some background information for Maureen and she published it as a guest blog on her site, but because of space limitations, she was only able to use an abridged version. Since I don’t have the same space limitations, I decided to publish the “unabridged” version here.

So, here is my story:

The Beginning of My Career in Chemistry

I graduated from the Univ. of Massachusetts in Amherst, MA in 1957 with a B.S. degree in organic chemistry. After three jobs in industry (The Refinery Technology Laboratory of Gulf Oil in Philadelphia – analyzing oils and gas products from the refinery; the Container & Sealant Lab at the Dewey & Almy Div. of WRGrace in Cambridge, MA – working on cap and can sealants for baby food and peanut butter jars and aerosol can valves; and The Exploratory Development Lab at United-Carr Inc. in Watertown, MA – working on adhesives to replace fasteners for automotive applications), I joined the staff of the Product Technology Section of Arthur D. Little (ADL) of Cambridge, MA, the international consulting firm, in March 1969, as a laboratory bench chemist.

Over my twenty-five years at ADL, I worked on hundreds of projects. Among the more memorial assignments were being part of the team that developed the “all plastic pencil” for the Empire Pencil Company (part of Hasbro Toy); working on the development of an erasable pen ink compound for Bic Pen; trying to produce a protective plastic liner for glass Thermos bottles (to protect the food contents of the bottles when school children hit their neighbors on the head with their lunch boxes – which proved a technical success – water, soup and coffee stayed hot overnight, but failed miserably, as the plastic liner took the flavor out of the coffee making it taste terrible!); developing a spin-cast epoxy eyeglass frame compound and manufacturing process for Universal Optical; developing an improved firefighter’s glove for NIOSH and NASA; the development of a unique, disposable, no moving-parts mixer for use in dispensing two-part epoxy and urethane adhesives for the MPB Corporation (now commonly used in all dentist’s offices for dispensing casting compounds and sold in hardware stores for delivering reactive adhesives and sealants); and of course being a part of the team that built and flew a lead balloon to prove that lead balloons really could fly! (In fact I tried to launch the silk purse made from sow’s ears in a basket beneath our lead balloon!)

I have written the stories behind many of the above inventions and products in my “other” blog, ADL Chronicles.

An Introduction to Soft Contact Lenses

One of my first assignments at ADL (along with working on chemically stabilizing soils for soft ground tunneling) was to see if there were other uses for hydroxy ethyl methacralate (HEMA), the material that soft contact lenses were composed of. National Patent Development Corp. (NPDC), which had acquired the Czech technology and licensed it to Baush & Lomb, wanted to know if this product could be used for other applications. We thought of applying it to the hull of boats to make them more slippery (and go faster in water and reduce adhesion of barnicles), but the best I could come up with was its use as a slow release reservoir for insecticides to kill mosquito larvae in swampy areas.

A few years later, in June 1972, and because of my knowledge of the properties of HEMA, NPDC asked me to lead a study on the “safety and efficacy” of the B&L Soflens, which had just been approved for marketing (March 1972). (NPDC was going to issue some stock to the public and the underwriters needed this due diligence report for the offering.) The study involved interviewing all of the original FDA clinical investigators for the Soflens. The knowledge about soft lenses I gained led to several papers about the “Outlook for Soft Lenses” that were published by ADL’s Decision Resource Division. Those publications led, over the next fifteen years, to over 150 assignments in the soft lens industry, including about 50 briefings to companies interested in both the technology and financial aspects of soft contact lenses. (How was B&L making so much money with their Soflens business?) It also led to my assisting Johnson&Johnson (Vistakon), Ciba Geigy (CibaVision), and Schering Plough (Wesley-Jessen) in their acquisitions of technology or small companies, to enter the soft lens industry. (In essence, I became the “guru” of the soft contact lens industry!)

Ophthalmology, Lasers and Writing

The soft lens assignments led to assessments of intraocular lenses (IOLs), plastic eyeglass lenses and eventually, in 1983, the just FDA-approved YAG ophthalmic lasers for correcting capsule opacities following cataract procedures. In 1985, I became involved with surgical lasers and in 1986 wrote the first comprehensive research and market report on medical lasers, “Medical Laser Systems: The Surgical Revolution”, that was published by Arthur D. Little’s Decision Resources Division. This was followed by a second comprehensive report on medical lasers, “The Outlook for Medical Lasers: The New Technologies”, published in 1988, also by Decision Resources. That led to my second career at ADL,  involving ophthalmic and medical laser consulting.

In the summer of 1985 I attended a Gordon Research Conference on lasers used with biological materials, where I met many of the leading researchers and surgeons involved in ophthalmic and medical laser technology. In December 1985, I was asked to prepare a market report about the potential for the excimer laser to correct vision. That report, about what I called LRK (Laser Photorefractive Keratectomy), became PRK, or ablation of the surface of the cornea to correct vision. My report was used to raise funds to begin one of the first excimer laser companies, Tauton Technologies (which later acquired VISX and assumed the VISX name).

That led to my entry into consulting in refractive lasers and writing the first market reports about refractive surgery in the mid-1980s and early 1990s. (I later wrote the seminal report on the future of laser refractive surgery for Summit Technoloy in 1992, wherein I predicted that the excimer laser would gain FDA marketing approval would occur by mid-1995. As I recall, I believe I was off by about 4 months.)

As I had begun attending ophthalmic and medical laser industry meetings (AAO, ASCRS, ARVO, ASLMS), I started writing about what I learned at those meetings. I first began writing columns for Vision Monday in 1988, mostly about my contact lens-related work. In 1989, I was asked to write a monthly column for Ophthalmology Management which became my Technology Update column. (Ophthalmology Management stopped publishing in the spring of 1991.) In the fall of 1991, Ocular Surgery News asked me to continue my Technology Update columns for them. This monthly feature, mostly covering new technologies that I discovered at the ophthalmic meetings, ran for over eleven year in OSN.

I was among the first to write about “custom ablation” and LASIK. One of my favorite titles from those times was, “Inlays, Onlays, Rings & Things” which described alternatives to laser refractive surgery.

Retirement and Spectrum Consulting

Finally, in March of 1994, on the anniversary of my 25th year with ADL, I retired from ADL and started my own consulting firm, Spectrum Consulting, continuing my consulting work in ophthalmics and medical lasers. In the fall of that year I started publishing Executive Laser Briefing, a monthly newsletter about current developments in the ophthalmic and medical laser industries. It was begun as an added service for my consulting clients, but I soon realized that others were interested in the publication. I began marketing the newsletter, which grew to a 40-60 page monthly publication, sent out to clients around the world, and it became a major part of my consulting business.

In December 2005, after eleven years, I  sold the newsletter and its client list to the publishers of Trends-In-Medicine, who continue to publish the newsletter today, renamed Executive Laser Report, and retired from active consulting.

A New Blogging Career Begins: Irv Arons’ Journal

That’s when I decided to begin writing my blog, Irv Arons’ Journal. It was originally started as a vehicle to place the more than 150 previously published articles online and accessible for historians and researchers, as I was involved in the beginning of several ophthalmic firsts – among them the birth of soft lenses, IOLs, ophthalmic lasers, refractive lasers, etc. Most of the articles were not available online because they were written prior to the explosion and availability of the web.

However, I quickly became diverted because I realized that I had insight into several new technologies that were entering ophthalmic use and I had access to those in the know who could provide me with the insight to write about these developments.

It all began because of some colleagues writing about what had happened the previous summer at the Retina 2005 Meeting in Montreal. Dr. Phil Rosenfeld presented information about his use of Avastin to stop the wet form of age-related macular degeneration (AMD) cold in its tracks and to provide improved vision to some patients. His presentation wowed the audience, but other than the retinal surgeons present at the meeting, no one else in the ophthalmic world was aware of the significance. I decided I needed to tell this story – Avastin: A New Hope for Treating AMD -- and so began my blogging career with an emphasis on new technologies for treating retinal diseases.

Since that start in December 2005, I now have over 270 articles posted online, mostly about new treatments for both dry and wet AMD, but also including writeups about new devices used to both treat and detect AMD.

Along the way, I have also written about the use of lasers to treat eye floaters, about the history and use of femtosecond lasers, including their use in treating cataracts, an overview of treatments for glaucoma, including the use of the then new SLT laser.

A Developing Interest in Stem Cells and Gene Therapy

Over the past several years, I became interested in the use, first of stem cells, and then gene therapy in the treatment of ophthalmic diseases. In September 2010 I wrote A Primer on the Use of Stem Cells in Ophthalmology, which was followed in November 2010 with my first writeup on the use of gene therapy in ophthalmology, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD. Since then, I have followed with more than 15 updates on stem cell treatments and more than a dozen for gene therapies.

In addition, I have put together comprehensive tables of the companies and institutions involved in both stem cells and gene therapies, the ophthalmic applications under evaluation, and data about the clinical trials underway and completed for both therapies. All of this information is now available online via my blog.

And, the Story Continues

I hope this overview has given you a glimpse into how I went from being a bench chemist to becoming an authoritative resource in the new technologies for treating ophthalmic diseases and conditions, starting at the front of the eye and working my way into the back of the eye.

For continual updates, please visit Irv Arons’ Journal and follow me on Twitter @iarons.

People in the NorthWest with X-linked retinoschisis

XLRS Natural History Study Beginning in Portland, Oregon

March 29, 2013 – Oregon Health & Science University (OHSU) is launching a three-year natural history study for people with X-linked retinoschisis (XLRS). Funded by the Foundation Fighting Blindness, the investigation’s primary goal is to identify outcome measures — such as changes in vision or retinal structure — that could be useful in evaluating the effectiveness of potential therapies in clinical trials. The study will also help determine the types of XLRS patients most suitable for future therapeutic studies.

Knowledge gained from the XLRS natural history study will aid in the design of an XLRS gene therapy clinical trial slated to begin in late 2014 or early 2015. The trial will be a collaboration between Applied Genetic Technologies Corporation, OHSU and the Foundation.

X-linked retinoschisis occurs almost exclusively in males. Participants in the natural history study must be of that gender. Otherwise, to qualify, they must:

• have a clinical diagnosis of XLRS
• have a disease-causing mutation in the gene RS1
• be 7 years of age or older
• be able to provide consent/assent (understand study procedures and risks)

Participants will need to make yearly visits to the Casey Eye Institute in Portland, Oregon. Some travel may be reimbursed.

If study participants are not already using carbonic anhydrase inhibitors (CAI), they will be offered this standard-of-care treatment during the study. If participants start CAI treatment during the study, they will need to travel to OHSU for some additional visits. CAIs are thought to reduce retinal edema (swelling) and other symptoms associated with XLRS.

For more information about the XLRS natural history study, contact the study coordinator at (503) 494-2363 or email at beattie@ohsu.edu.

Gene Therapy in Ophthalmology Update 18: A RetroSense Update

I first learned about the potential of using gene therapies in treating ophthalmic disorders back in November 2010. That’s when I was introduced to gene therapy by Sean Ainsworth, the founder and CEO of RetroSense Therapeutics. I haven’t written about this company or the unique approach it is taking to try and treat retinitis pigmentosa and the dry form of AMD since that first article, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD. With several news events occurring with the company recently, I felt it was time to bring readers of this blog up-to-date.

First, a brief review of the approach that RetroSense is taking. The technology that the company is using was developed at Wayne State University by Dr. Zhuo-Hua Pan. It involves using channelrhodopsin-2, delivered via an adeno-associated viral vector (AAV) directly into the retina to restore lost vision. Channelrhodopsin-2 is an “opsin”, derived from green algae which can be used to convert light-sensitive inner retinal neurons into photoreceptor cells, thereby imparting light sensitivity to retinas that lack photoreceptors. This is a process called “optogenetic therapy”.

As reported in Retina Today(1), “We took a new strategy for restoring vision by genetically converting the retina’s second- or third-order cells to become light sensitive to mimic the function of rods and cones,” wrote Dr. Pan. “But critical to this strategy, we needed to find certain suitable light sensors that can be easily inserted into these surviving retinal cells.”

Optogenetics is defined(2) as, “...the 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 an interesting write-up about both optogenetics and RetroSense, Susan Young writing for MIT’s Technology Review(3), said, “The idea behind Retrosense's experimental therapy is to use optogenetics to treat patients who have lost their vision due to retinal degenerative diseases such as retinitis pigmentosa. Patients with retinitis pigmentosa experience progressive and irreversible vision loss because the rods and cones of their eyes die due to an inherited condition.”

She went on to say, “Retrosense is developing a treatment in which other cells in the retina could take the place of the rods and cones, cells which convert light into electrical signals. The company is targeting a group of neurons in the eye called ganglion cells. Normally, ganglion cells don't respond to light. Instead, they act as a conduit for electrical information sent from the retina's rods and cones. The ganglion cells then transmit visual information directly to the brain.”

“Doctors would inject a non-disease causing virus into a patient's eye. The virus would carry the genetic information needed to produce the light-sensitive channel proteins in the ganglion cells. Normally, rods, cones, and other cells translate light information into a code of neuron-firing patterns that is then transmitted via the ganglion cells into the brain. Since Retrosense's therapy would bypass that information processing, it may require the brain to learn how to interpret the signals.”

Before I relate the latest news about the company, I would like to share one further write-up about the company’s technology. This brief appeared in February, as part of an article in Popular Science entitled, “How Neuroscience Will Fight Five Age-Old Afflictions(4)”. One of the “afflictions” noted was blindness, and the writeup described RetroSenses’ approach to curing that affliction.

BLINDNESS

Gene therapy converts cells into photoreceptors, restoring eyesight

Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.

In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.

A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.

The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”

Rewiring The Brain: Blindness: a) An eye diseased with retinitis pigmentosa has damaged photoreceptors, or rods and cones. Doctors inject the eye with a nonharmful virus containing the gene channelrhodopsin-2, or ChR2. b) The virus migrates into the retina at the back of the eye and inserts the gene into ganglion cells, which relay signals from the rods and cones to the optic nerve. The ganglion cells begin expressing the ChR2 protein in their membranes. c) Incoming light activates the ChR2 protein in ganglion cells, stimulating them to fire an electrical impulse. That message travels through the optic nerve to the brain’s visual cortex, which interprets it as a rough image.  Medi-Mation (Used courtesy of Popular Science)

What’s New

Within the past few weeks, the company has made two important announcements relative to its intellectual properties:

On March 5th, the company announced the notice of allowance for a new U.S. Patent Application broadly covering optogenetic approaches to vision restoration. The Patent Application broadly covers methods of restoring visual responses with a variety of optogenetic compounds. Specifically, the allowed application includes claims covering methods of restoring visual responses by delivering channelrhodopsin and variants thereof, as well as halorhodopsin to retinal neurons - with or without the use of cell-type specific promoters, including mGluR6 (Grm6). The subject opsins have been studied extensively and published on as means of vision restoration in retinal degenerative conditions such as retinitis pigmentosa and dry age-related macular degeneration.

The approved patent application is part of the "Pan" patent family, which stems from the novel research of Dr. Zhuo-Hua Pan and others at Wayne State University and Salus University, designed to restore vision in retinal degenerative conditions. Several Pan patent applications are part of RetroSense's intellectual property estate, which focuses on optogenetic gene therapies and complementary devices for vision restoration.

"We are pleased that the U.S. Patent Office has allowed this patent application, which will substantively expand the coverage of RetroSense's intellectual property estate. RetroSense continues to develop novel intellectual property in the area of optogenetics. Accordingly, we plan to continue to extend our basic patent protections on our technologies. We have also maintained an ongoing strategy to consolidate key intellectual property required to develop and commercialize optogenetics to restore visual responses," said Sean Ainsworth, Chief Executive Officer of RetroSense.

And, on March 27th, the company announced an exclusive option to intellectual property covering vision augmentation from Massachusetts General Hospital. This gives RetroSense the right to an exclusive, worldwide license to the patent application "Method for Augmenting Vision in Persons Suffering from Photoreceptor Cell Degeneration", based on the research of Dr. Richard Masland, director of the Cellular Neurobiology Laboratory in the MGH Department of Neurosurgery.

“This is an exciting development for RetroSense Therapeutics, as Dr. Masland’s work at Massachusetts General Hospital has been tremendous,” stated Sean Ainsworth, CEO of RetroSense Therapeutics. “This intellectual property broadens our reach and strengthens our existing position in optogenetic approaches to vision restoration.”

Dr. Masland stated, “The goal of the work we have done so far is to find a therapy that can help restore some level of vision to people who are now blind from retinal disease. I look forward to moving forward with this work.”

The next step for the company is to begin a Phase I human clinical trial. As noted in the Popular Science article, the company believes that is likely to occur sometime next year.

References:

1. Novel Optogenetic Therapy May Restore Vision After Retinal Degeneration, Callan Navitsky, Assoc. Editor, Retina Today, April 2012.

2.  From Wikipedia.

3 Company Aims to Cure Blindness with Optogenetics, Susan Young, MIT Technology Review, August 28, 2012..

4.  How Neuroscience Will Fight Five Age-Old Afflictions, Virginia Hughes, Popular Science, Feb. 18, 2013.

Gene Therapy in Ophthalmology Update 17: Hemera Biosciences Obtains Initial Funding

In December 2011, following that year’s AAO Meeting, I wrote about Hemera Biosciences and its complement regulation therapy via the use of gene therapy to prevent membrane attack complex (MAC), the final stage of the complement cascade that is implicated in both dry and wet AMD. (Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD)

I am now happy to report that Hemera has obtained initial funding, along with the issuance of a US Patent and can now begin manufacturing its drug, soluble CD59 (protectin), perform animal toxicology and initiate a phase 1 clinical study.

To review, HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

The primary focus for the company will be preventing the conversion of the dry form of AMD from progressing into the wet form, however, they think that there's a role for HMR59 in treating the dry form (drusen and GA) as well as wet (neovascular) AMD.

Here is the company’s news release:

Hemera Biosciences Raises $3.75 Million; Patent Issued for TreatingAge-related Macular Degeneration

BOSTON, MA (March 15, 2013)  Hemera Biosciences announced its Series A financing of $3.75 million and issuance of US Patent 8,324,182 B2 on December 4, 2012, for treating age-related macular degeneration (AMD) with a human protein, soluble CD59 -- otherwise known as protectin.

“Human genetic studies and preclinical research have shown that alterations in complement – a significant driver of inflammation -- play a key role in the development of both wet and dry AMD,” said Adam Rogers, MD, one of the founders of Hemera. 

Preclinical studies done in the laboratory of Rajendra Kumar-Singh, PhD, another Hemera founder, have shown that intravitreal injection of an adeno-associated virus  that expresses soluble CD59, in an animal model, prevents the development of choroidal neovascularization. Choroidal neovascularization is the leading cause of  severe vision loss due to the wet form of AMD.

“Membrane attack complex (MAC) formation is the last step in the complement inflammation pathway.  Soluble CD59 when expressed in our animal models using gene therapy, prevents the development of MAC, death of retinal pigment epithelial cells and prevents abnormal blood vessel development in the eye.  Use of gene therapy to express soluble CD59 allows for long term treatment for this chronic blinding disease,” said Dr. Kumar Singh.

With the $3.75 million of financing raised in this initial round of funding, Hemera expects to have sufficient resources to manufacture the drug, perform animal toxicology studies and initiate a phase 1 study.

The founders and management team include Elias Reichel, MD, Jay Duker, MD, Rajendra Kumar-Singh PhD , and Adam Rogers, MD who all are on faculty at Tufts University School of Medicine.

About Hemera

Hemera Biosciences, founded in 2010, is a private company headquartered in Boston, Massachusetts that focuses on developing and commercializing gene therapy for age-related macular degeneration and other ocular conditions.

Hemera is developing its proprietary soluble CD59 gene therapy technology as a treatment for age-related macular degeneration for both the dry and wet forms of the disease.  The company’s lead program is the first and only complement therapy that directly targets MAC.  Hemera was started by some of the world’s leading experts in AMD and gene therapy.

INDEX/SEARCH

INDEX/SEARCH

For your convenience, and because only the last ten posts are shown on the opening page, here is a means for finding all of my posts in an easy-to-use fashion.

Use the Blog Search box in the upper left-hand corner of the header above, enter  "Menu" and click on "enter" and menus for most of my 250 or so postings will come up in an easy to search/find method (including short descriptions and live links.)

Oraya IRay Update 2: INTREPID Two-year Results Meet Primary Clinical Endpoint – Results in At Least 35% Fewer anti-VEGF Injections -- Oraya Joins with Optegra to Provide Treatments in the UK

The last time we checked in on Oraya in May 2011, the company had announced it had completed enrollment in its INTREPID clinical trial, being conducted at seven European sites with the enrollment of a minimum of 150 patients. (Oraya IRay Update: Company Completes Enrollment in European Clinical Trial)

The INTREPID trial is the first sham-controlled double-masked study to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. A total of 21 sites in five European countries participated in the trial with a total enrollment of 230 subjects.

During the EURORETINA Congress, held in Milan, Italy, at the end of September 2012, Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator for the trial, presented the results during the program’s AMD session. He reported that the trial achieved its primary end point demonstrating a statistically significant reduction in as-needed injections after one year. The actively treated patients required approximately 35 percent fewer injections than the sham group with similar or in some cases, better visual acuity outcomes. No radiation-related adverse events were experienced at the one year end point; including 60 subjects already at two year follow up. In addition, a defined population sub-group comprised of roughly half of the study participants experienced even lower injection rates while exhibiting meaningful vision benefit compared to sham.

Jackson stated that, “The year one results of the INTREPID trial are very encouraging for people with wet AMD—the prospect of fewer eye injections will appeal to all those receiving anti-VEGF therapy, and for certain subsets there is the added advantage of an improved visual outcome. Whilst it will be important to monitor safety over a longer period, the results so far suggest a favorable safety profile.”

Jim Taylor, CEO of Oraya Therapeutics, added, “We are very pleased that the results of the  INTREPID trial have validated the benefits of the Oraya Therapy for patients, clinicians and health  care providers. It is rare to have a new therapy that demonstrates improved patient outcomes while simultaneously offering the potential to significantly reduce treatment burden and costs. To have these benefits validated in a rigorous clinical trial is very rewarding, and we are exceptionally grateful to the patients and clinicians who participated in this important study.”

Then, the following month, at the British and Eire Association of Vitreoretinal Surgeons (BEAVRS) meeting in Dublin, Dr. Jackson presented a further analysis of the INTREPID results, discussing an analysis of the best responders in the INTREPID trial showing that anti-VEGF injections were reduced by 54% in the patient sub-group characterized by the presence of significant fluid and smaller lesion size.

Dr Jackson said: “A post-hoc analysis looked for the best responders to stereotactic radiotherapy and found that they had significant fluid at baseline and a lesion size of 4 mm or less in greatest linear dimension.”

“This dimension corresponds to the diameter of the spot beam (90% isodose) projected onto the retina by the IRay device. The 26% of patients with both of these characteristics not only had a reduction of 54% in the number of PRN injections but also a mean vision superiority of 6.8 ETDRS letters compared to equivalent patients in the control group.”

Dr Jackson added: “The one-year results of the INTREPID study are encouraging for clinicians and for individuals with neovascular AMD. The prospect of needing fewer eye injections will appeal to any patient receiving anti-VEGF therapy, and for certain sub-sets there is the added advantage of an improved visual outcome. The study showed a favorable safety profile for the procedure, and safety review is ongoing to detect any later effects of the radiotherapy treatment.”

Oraya Therapeutics Joins Forces with Optegra Eye Hospital Group

In December 2012, Oraya Therapeutics, Inc. announced that an agreement had been reached with UK specialist eye hospital group Optegra, to establish Optegra as the world’s first clinical centers to offer Oraya Therapy Stereotactic Radiotherapy for the treatment of wet Age-related Macular Degeneration (AMD).

The agreement was reached shortly after Oraya released data from a successfully completed clinical trial (The INTREPID Study) involving 21 sites and conducted in the UK and four other European countries.

Ophthalmic surgeon at Optegra, Andy Luff, commented: “Wet AMD currently affects approximately 260,000 people in the UK2, and it is projected that nearly 40,000 new people will be affected each year. The chronic injection therapies currently in use often require six to eight injections per year placing an unsustainable and costly burden on the National Health Service (NHS), on patients and on their families.”

Gareth Steer, Managing Director for Optegra, said: “Optegra is excited to have been selected to offer the Oraya Therapy as a treatment option that can help to mitigate this critical problem. We are pleased to have the opportunity to work with the innovative and dedicated people of Oraya, and to have the benefit of a scientifically sound clinical trial to support the value and potential of this unique therapy.”

In commenting on the choice of Optegra and the UK for the global introduction of the therapy, Jim Taylor, CEO of Oraya Therapeutics, said: “We are exceptionally proud and pleased to have partnered with Optegra, an organization that shares our values regarding the importance of good science, a focus on services that offer better patient outcomes and greater cost effectiveness, and with a commitment to the highest standards of quality and patient care. Bringing the therapy to the UK also provides us the opportunity to address a recognized and urgent need within the NHS for better therapeutic solutions, and we look forward to working with Optegra and the NHS to expand the access and availability of this important therapy in the months ahead.”

Finally, at the end of February 2013, the company announced that one of the patients who successfully was treated for wet age-related macular degeneration (AMD) with Oraya Therapy during the INTREPID clinical trial has released data showing he has experienced significant, sustained vision improvement more than two years after treatment in his right eye, without any subsequent anti-vascular endothelial growth factor (anti-VEGF) injections or other treatment. The patient, well-known British author Jonathan Gathorne-Hardy, also said he had experienced significantly reduced central vision in his left eye following standard anti-VEGF treatments over the same time period.

Oraya president and CEO Jim Taylor commented, “These life-changing results for patients with wet AMD further underline the efficacy of Oraya Therapy, and are the real source of motivation behind all that we do. With the ability to improve the vision of wet AMD patients with fewer injections – and in this case no injections at all – Oraya Therapy can offer a more convenient, effective and cost-effective treatment for this debilitating disease.”

Mr. Gathorne-Hardy was one of 230 patients enrolled in the multi-national INTREPID study evaluating the 20-minute, non-invasive therapy. He has wet AMD in both eyes, and received he Oraya Therapy at King’s College Hospital, London on his right eye in August 2010. After one year, the visual acuity in his right eye was significantly improved, with a vision gain of nine letters on his visual acuity score, and after two years has stabilized at an acuity better than before the Oraya Therapy. He has not received any subsequent anti-VEGF injections into the eye or any other treatment. In contrast, the central vision of Mr. Gathorne-Hardy’s left eye, diagnosed in 2008 and treated solely with the standard anti-VEGF injections, was significantly reduced.

All patients in the INTREPID trial previously had received at least three anti-VEGF injections in the prior year and required further anti-VEGF treatment. Within two weeks of receiving the injection, one-third of the subjects received a sham exposure and the remainder received a radiation dose of either 16 or 24 Gray (Gy). They were then followed monthly and treated with anti-VEGF (Lucentis) as needed according to specified reinjection criteria.

Results of the trial showed that further injections were reduced by 32 percent in the radiotherapy groups compared with the control group. These radiotherapy groups were twice as likely to receive no injection over the course of a year and were approximately half as likely to need four or more injections over the course of a year. Also, post-hoc analysis looked at the best responders to stereotactic radiotherapy and identified a group of patients which experienced a 54 percent reduction in the number of injections and a mean visual superiority of 6.8 ETDRS letters compared to equivalent patients in the control group.

“The results of the INTREPID study which have been reported to date are encouraging for clinicians and for individuals with wet AMD. The prospect of maintaining vision while needing fewer eye injections will appeal to any patient receiving anti-VEGF therapy, and for certain subsets in the trial there is the added advantage of an improved visual outcome,” said Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator for the trial.

The Oraya Therapy is now available at the Optegra Surrey Eye Hospital in Guildford, United  Kingdom, establishing Optegra as the world’s first clinical centre to offer Oraya Therapy.

Tim Clover, CEO of Optegra, said: “Optegra treats many patients with AMD and knows the frustration of managing this disease. We are committed to encouraging new therapies that ill have a positive impact on patients. Oraya Therapy offers a real benefit to patients and Optegra is proud and excited to be selected as Oraya’s launch partner. We are pleased to have the opportunity to work with the innovative and dedicated people of Oraya, and to have the benefit of a scientifically sound clinical trial to support the value and potential of this unique therapy.”

Status of U.S. Clinical Trials:

When asked about progress towards U.S. clinical trials, Jim Taylor, CEO of Oraya responded with this, “On the topic of (the) U.S., the results from the INTREPID trial provide us a clear understanding of the trial design most appropriate and suitable for the FDA process; and with a high probability of success. The company is currently raising the capital needed to support the initial commercialization efforts in Europe, and that funding might also support the implementation of the US trial. Decisions on when to initiate the US trial will be based on the availability of that financing.”

For a full report on the Oraya IRay system and how it works, see my first writeup from November 2009: Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

Reference Links: 

Company News Releases

Sept 20, 2012
http://www.orayainc.com/wp-content/uploads/2012/09/Oraya-EURETINA-release-FINAL.pdf

November 22, 2012
http://www.orayainc.com/wp-content/uploads/2012/11/ORAYA-_BEAVRS_PR_22Nov2012_FINAL.pdf 

Dec. 11, 2012
http://www.orayainc.com/wp-content/uploads/2012/02/OrayaOptegraReleaseFINALGlobal.pdf

Feb 27, 2013
http://www.orayainc.com/wp-content/uploads/2013/03/Intrepid_Results_FINAL_022713.pdf