Saturday, March 30, 2013

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

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.


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.


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.

Monday, March 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.

Tuesday, March 05, 2013

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