AMD Update 16: Visualization of Drusen and RPE With New Software Application for Zeiss HD-OCT: A New Aid for Assessing Both Dry and Wet AMD

As noted below, by both Drs. Rosenfeld and Puliafito, this new diagnostic tool will play an important role in assessing and speeding the development of new treatments for both dry and wet AMD that are being researched and brought to the market.

In an announcement on January 20th, Carl Zeiss Meditec said that it had added new dry age-related macular degeneration (Dry AMD) and new glaucoma diagnostic tools for its Cirrus HD-OCT (High Definition Optical Coherence Tomography), and the new software, version 6.0, had received clearance from the US Food and Drug Administration (FDA).

Zeiss Meditec Cirrus HD-OCT

"Designed to help ophthalmologists manage the growing number of patients with serious eye diseases, the new Cirrus application package offers a more comprehensive approach to disease management, delivering more thorough and more meaningful clinical analysis within the retina and glaucoma workplaces", said Dr. Ludwin Monz, President and CEO of Carl Zeiss Meditec AG.

The new Cirrus HD-OCT retina application provides Advanced Retinal Pigment Epithelium (RPE) Analysis, which enables clinicians to objectively monitor changes associated with dry AMD. The application tracks change in RPE elevation area and volume often associated with drusen. It also identifies and measures the area of transparent regions in the RPE that can develop with geographic atrophy. Unlike blue light fundus autofluorescence (FAF), Cirrus measurements are not affected by macular pigment in the fovea and provide an objective assessment of geographic atrophy status as part of a standard OCT exam.

Further expanding Carl Zeiss Meditec's retina workplace, the Cirrus HD-OCT application package also includes Enhanced Depth Imaging (EDI), which allows for better visualization of deeper tissues, such as the choroid, enabling doctors to better understand the role of this anatomy in retinal disease.

A Look at the Retinal Layers Able to be Visualized

"The new integrated RPE Analysis software now offers clinicians the opportunity to objectively analyze all stages of AMD, especially the progression of dry AMD. Now one imaging technique, the Cirrus HD-OCT, can quantitate drusen and geographic atrophy, as well as choroidal neovascularization (CNV) and any elevation of the RPE associated with wet AMD," said Dr. Philip J. Rosenfeld, Professor of Ophthalmology at the Bascom Palmer Eye Institute and collaborator with Carl Zeiss Meditec in developing the techniques underlying the new applications. "Now we don't have to move patients between different instruments to visualize drusen, geographic atrophy, and CNV. These analyses will help clinicians stage and monitor disease progression today and will be critical to managing response to therapy as new treatments come to market."

As pointed out by Carmen Puliafito, MD, speaking at Retina 2012, held last week in Hawaii, “New algorithms to translate spectral domain optical coherence tomography images have begun to allow retinal specialists to measure drusen volume and area for the first time and may offer a better understanding of age-related macular degeneration. We now have some really objective tools that we can use to look at disease progression and then perhaps come to a better understanding of the pathophysiology of what exactly this disease is."

Fundus photography allows ophthalmologists to see drusen, but trying to count or measure it is nearly impossible, Dr. Puliafito said. These new methods will allow ophthalmologists to view the internal limiting membrane and the retinal pigment epithelium and where the retinal pigment epithelium should be, resulting in elevations that correspond to drusen, he said. This provides a major step forward in quantification.

"Drusen come, drusen go. And in their wake can be geographic atrophy, choroidal neovascularization or absolutely nothing," Dr. Puliafito said. "We now have some really objective tools to look at disease progression" to better understand AMD.

The new Cirrus HD-OCT application package also extends Carl Zeiss Meditec`s comprehensive suite of glaucoma diagnostic tools, adding new Ganglion Cell Analysis and Optic Nerve Head Progression Analysis. The Ganglion Cell Analysis evaluates the thickness of the combined ganglion cell and inner plexiform layers and compares the results to normative data. The new software package also expands Guided Progression Analysis (GPA) to automatically track progression of average cup-to-disc ratio and other optic nerve head parameters.

With these new clinical applications, Cirrus HD-OCT now spans the full spectrum of visualization and structural assessment in glaucoma: angle assessment, central corneal thickness measurement and analyses of retinal nerve fiber layer, ganglion cell layer and optic nerve head.

The new software package addresses a global market by adding user interfaces in Japanese, Chinese, Korean, German, French, Italian and Spanish to the original English interface. The software received its CE mark for distribution to major European markets in November, 2011.

Stem Cells in Ophthalmology Update 16: Results of First Embryonic Stem Cells in Treatment of Eye Disease Reported in Peer-Reviewed Journal

Two significant events were reported today by Advanced Cell Technology. First, the company said that a peer-reviewed publication of clinical results from its first patients treated at UCLA Jules Stein Eye Institute had been placed online by the UK’s The Lancet. The study reported on the four-month results of a safety study initiated in human patients last July. In that study, one eye of a patient with Stargardt’s macular dystrophy (SMD), and another with the dry form of AMD were given doses of human embryonic stem cell-derived retinal pigment epithelial (RPE) cells.

The second event was the announcement that the first patient had been treated with stem cells in the UK arm of the Stargardt’s study, at Moorfields Eye Hospital last Friday. (See Update 10 for more information.)

As reported in The Lancet article, Embryonic Stem Cell Trials for Macular Degeneration: A Preliminary Report, in addition to showing no adverse safety issues, structural evidence confirmed that the hESC-derived cells survived and continued to persist during the study period reported. Both patients had measurable improvements in their vision that persisted for more than four months.

As noted by the lead author (Dr. Steven Schwartz), in his findings: “Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behavior and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt’s macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).”

At four months following treatment, no hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection were observed in either patient at any time. Detailed clinical and diagnostic laboratory assessments were performed at multiple post-transplantation evaluations. Abnormal growth (or tumor formation) would be considered a significant safety concern for stem-cell based therapies, in particular those derived from hESCs due to their pluripotency; it is therefore critical to control the differentiation of hESCs. Results reported indicate that stem cell differentiation was well controlled in these patients. No adverse safety signals were detected.

Anatomic evidence of successful stem cell derived RPE transplantation was observed clinically and with high resolution imaging technology in the patient with SMD. This evidence included increasing pigmentation at the level of RPE, within the area of the transplant, beginning one week after transplantation and throughout the follow-up period. Transplanted stem cell derived RPE appeared to engraft in the proper location and assume normal RPE morphology. Engraftment and increasing pigmentation were not detected in the dry AMD patient. However, both patients showed some visual improvement at the four month follow-up period. (Emphasis added by editor.)

Measuring visual improvement in patients with very low vision is difficult, and no regulatory consensus exists regarding on how best to measure visual changes in these patients. As reported in The Lancet, the visual acuity of the Stargardt's patient improved from hand motions only to 20/800 vision. Before treatment, the patient was unable to read any letter on the ETDRS visual acuity chart. However, by two weeks post-transplantation, she was able to start reading letters, which improved to five letters at one to three months in the treated eye.

"It has been over a decade since the discovery of human embryonic stem cells," said Robert Lanza, M.D., chief scientific officer of ACT, and co-senior author of the paper. "This is the first report of hESC-derived cells transplanted into patients, and the safety and engraftment data to date look very encouraging. Although several new drugs are available for the treatment of the wet type of AMD, no proven treatments currently exist for either dry AMD or Stargardt's disease. Despite the progressive nature of these conditions, the vision of both patients appears to have improved after transplantation of the cells, even at the lowest dosage. This is particularly important, since the ultimate goal of this therapy will be to treat patients earlier in the course of the disease where more significant results might potentially be expected. We would like to thank the patients for their willingness to participate in these safety studies. It has provided the scientific community with important data and experience that will help advance efforts in the regenerative medicine field."

Human embryonic stem cells can provide a superior source of replacement tissue by producing an unlimited number of healthy "young" cells with potentially reduced immunogenicity. The eye is an immune privileged site due to the protection of the subretinal space by a blood-ocular barrier, and as a result only low and transient doses of immunosuppression were used. No signs of rejection or inflammation were observed in either patient, and doctors will continue to monitor both patients.

"We are extremely pleased with these first clinical results from our ongoing studies to determine the safety and tolerability of subretinal transplantation of hESC-derived RPE cells," said Gary Rabin, chairman and CEO of ACT. "This represents an important milestone not only for ACT and UCLA"s Jules Stein Eye Institute but also for the field of regenerative medicine. The publication of these data in The Lancet demonstrates their quality and importance. We would like to thank the team, patients and principal investigator for their contributions to this study which have resulted in this outstanding publication. The data underscore the potential of stem cell therapies and regenerative medicine to realize the possibility repairing or replacing tissues damaged from disease. We are looking forward to the continuation of our clinical programs and the generation of additional data."

The hESC-derived RPE cells underwent extensive safety studies prior to transplantation. The cells were confirmed to be free of animal and human pathogens, and a high sensitivity assay was performed to rule out the presence of any undifferentiated hESCs in the final product, a risk factor for tumor formation. Controlled hESC differentiation resulted in near-100 percent pure RPE. A central feature of hESCs is that the stage of in vitro differentiation can be controlled to maximize survival and functionality. The data here show that the extent of RPE maturity and pigmentation may dramatically impact subsequent attachment and growth of the cells after transplantation.

"It is an honor to initiate the translational research process as we begin to take stem cell biology out of the laboratory and into the operating room," said Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute, principal investigator of the study and author of the publication. "The scientific and regulatory teams, as well as the leadership at ACT have been exemplary. Recognizing that we are reporting positive preliminary safety data, and a functional signal that there may be a biological benefit to patients in terms of visual increase, makes this is an exciting time for ophthalmology and regenerative medicine."

Both trials are prospective, open-label studies designed to determine the safety and tolerability of hESC-derived RPE cells following sub-retinal transplantation into patients with SMD and dry AMD at 12 months, the studies' primary endpoint. Each trial will enroll 12 patients each, with cohorts of three patients each in an ascending dosage format. Both the SMD and dry AMD patient had subretinal transplantation of the smallest dose (50,000 cells) of fully-differentiated RPE cells derived from hESCs.

The paper's other authors are Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K. Pan, and Rosaleen M Ostrick at UCLA and the Jules Stein Institute; and Edmund Mickunas, Roger Gay, and Irina Klimanskaya at ACT.

Editor’s Note: It should be noted that the smallest dosage allowed was used in these first patients in a safety study, in severely affected patients. Although some vision improvement was noted, it should be expected that higher doses, and in less-affected patients, might provide even better outcomes. Time will tell.

Stem Cells in Ophthalmology Update 15: Wills Eye Joins ACT’s Clinical Trials for Dry AMD Using Embryonic Stem Cell-derived RPE

Advanced Cell Technology announced yesterday that the Wills Eye Institute in Philadelphia had received institutional review board (IRB) approval to become a site for the Phase I/II clinical trial for dry age-related macular degeneration (Dry AMD) using human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells. Wills will join UCLA’s Jules Stein Eye Institute and Moorfields Eye Hospital in London as sites participating in the clinical trials for Dry AMD, under ACT’s National Clinical Trials protocols.

"The participation of Wills Eye Institute in this trial will significantly enhance our clinical program," said Robert Lanza, M.D., ACT's chief scientific officer. "Wills Eye Institute is the oldest eye-care facility in the United States and is consistently ranked as one of the best ophthalmology hospitals in the country by the U.S. News & World Report. We are looking forward to working with Dr. Regillo and his team to address the unmet medical needs of degenerative diseases of the retina. With this latest approval, the company continues to assemble a clinical team that includes the best eye hospitals and surgeons in the world in our effort to find an effective therapy for this devastating eye disease."

The Phase I/II trial for dry AMD is a prospective, open-label study designed to determine the safety and tolerability of the hESC-derived RPE cells following sub-retinal transplantation into patients with dry AMD. The trial will ultimately enroll 12 patients, with cohorts of three patients each in an ascending dosage format. Which patients will be enrolled at the Wills Eye Institute will be determined in the near future.

"Degenerative diseases of the retina often lead to a significant visual impairment," said Carl Regillo, M.D., director of clinical retina research at Wills Eye Institute and professor of ophthalmology at Thomas Jefferson University. "Replacing lost or damaged cells with functional and healthy cells may provide a treatment option that could slow vision loss, and perhaps even reverse the effects of disease. We are looking forward to collaborating with ACT to evaluate the potential of the stem cell-derived RPE cells for debilitating diseases such as Stargardt's macular dystrophy and dry AMD."

Dry AMD, or "central geographic atrophy," is the "dry" form of advanced age-related macular degeneration. Dry AMD occurs when the light-sensitive cells (photoreceptors) in the macula slowly break down, gradually blurring central vision in the affected eye. Over time, as less of the macula functions, central vision is gradually lost in the affected eye, often progressing to blindness. The loss of photoreceptors is a direct result of a preceding degeneration of the retinal pigment epithelial (RPE) layer of cells just below the retina. As many as 30 million people in the United States and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed. Approximately 10% of people ages 66 to 74 will have symptoms of macular degeneration, the vast majority suffering from the "dry" form of AMD -- which is currently untreatable. The prevalence increases to 30% in patients 75 to 85 years of age.

"We are honored to have the opportunity to work with one of the foremost eye care centers in the world", said Gary Rabin, chairman and chief executive officer of ACT. "This clinical trial represents the culmination of years of innovation and hard work by ACT's scientific team. The whole world is focused on our trials, most especially patients suffering from dry AMD and other forms of macular degeneration. Wills Eye Institute has a strong tradition of innovation and discovery, and we are excited at their participation in bringing this cutting-edge technology through the clinic."

Additional details about these studies, for which the Jules Stein Institute at the University of California, Los Angeles and Moorfields Eye Hospital in London have also received IRB approval, can be found at ClinicalTrials.gov Identifier: NCT01344993.

Editors Note: As noted in the above quote from Dr. Regillo, it can be speculated that Wills Eye will soon join both Jules Stein and Moorfields in also treating Stargardt’s disease, under ACT’s National Clinical Trials NCT01345006 and NCT01469832.

It should also be noted that Wills Eye is also one of the clinical sites participating in the Centecor (J&J) clinical study of Dry AMD using adult stem cells from umbilical cord blood, NTC01226628.

Breaking News – as of January 19th, Wills Eye had been added to ACT’s clinical protocol for treating Dry AMD with embryonic stem cell-derived RPE cells, and was actively recruiting patients.

About Wills Eye Institute

Wills Eye Institute is a global leader in ophthalmology, established in 1832 as the nation's first hospital specializing in eye care. U.S. News & World Report has consistently ranked Wills Eye as one of America's top three ophthalmology centers since the survey began in 1990. Wills Eye is a premier training site for all levels of medical education. Its resident and post-graduate training programs are among the most competitive in the country. One of the core strengths of Wills is the close connection between innovative research and advanced patient care. Wills provides the full range of primary and subspecialty eye care for improving and preserving sight, including cataract, cornea, retina, emergency care, glaucoma, neuro-ophthalmology, ocular oncology, oculoplastics, pathology, pediatric ophthalmology and ocular genetics, refractive surgery and retina. Ocular Services include the Wills Laser Correction Center, Low Vision Service, and Diagnostic Center. Its 24/7 Emergency Service is the only one of its kind in the region. Wills Eye also has a network of nine multi-specialty, ambulatory surgery centers throughout the tri-state area. To learn more, please visit www.willseye.org .

Gene Therapy in Ophthalmology Update 8: Promising Results in the Treatment of Leber’s Congenital Amaurosis (LCA)

As noted in the Gene Therapy in Ophthalmology by Application table shown in Update 7, there are seven clinical trials underway at various institutions aimed at the treatment of Leber’s Disease. Some of these trials have been underway for several years with multiple patients having been treated.

When I sent a copy of the table to Dr. Stephen Rose, chief research officer for the Foundation Fighting Blindness for comments and review, I also asked the question, “Who is tracking and reporting on the results of the patients already treated?” I didn’t get a direct response, but a few days later, the FFB reported the following story on its web site, providing some insight into the results being obtained.

Pennsylvania-Florida Team Reports Promising Three-Year Results for LCA Clinical Trial

Foundation Fighting Blindness

January 13, 2012 - Three years after it began, the landmark Phase I gene therapy clinical trial for people with Leber congenital amaurosis (LCA) at the Universities of Pennsylvania and Florida (NCT00481546) continues to go very well. Overall safety and vision improvements have been sustained. All 15 participants in the study, ranging in age from 11 to 30, have demonstrated vision improvement to varying degrees, including increases in visual field, night vision and mobility. Improvements in visual acuity only occurred in those who entered the trial with the lowest visual acuity.

"We are extremely pleased with the latest report coming from the Penn-Florida study. It is imperative that we demonstrate long-term safety and effectiveness of the treatment, and the team is doing that superbly," says Dr. Stephen Rose, chief research officer, Foundation Fighting Blindness. "We are also impressed by the depth and scope of their analyses of the treatment, which not only validate their results, but will greatly increase the chances of success for future gene therapy clinical trials for LCA and other retinal diseases."

The University of Pennsylvania's Dr. Samuel Jacobson, lead investigator for the clinical trial, and Dr. Artur Cideciyan, his co-investigator, say their team has learned that targeting certain areas of the retina for injection of the treatment is critical to both safety and effectiveness. Specifically, injections underneath the fovea, the central area of the retina with the highest concentration of cones, didn't improve vision and could potentially lead to damage or detachment. They believe that a strategy of two or three injections at different points outside the fovea will be optimal for treating many of these LCA patients.

Dr. William Hauswirth, a Foundation-funded gene therapy development expert and trial co-investigator from the University of Florida, is conducting lab studies of a gene therapy injection approach that may reduce the overall risk of retinal damage and detachment. As a potentially safer alternative to subretinal injections, he is evaluating intravitreal injections made near the front of the retina. The challenge with the intravitreal approach is ensuring that the treatment, which is contained in a tiny drop of liquid, gets to the retinal cells that need it. Dr. Hauswirth notes that different injection sites and strategies might be warranted for different diseases.

In addition to the Universities of Pennsylvania and Florida study, four other clinical trials are underway for gene therapy for LCA caused by mutations in the RPE65 gene. Those studies are being conducted by: The Children's Hospital of Philadelphia (CHOP), Moorfields Eye Hospital in London, Hadassah Medical Organization in Jerusalem, and Oregon Health & Science University, for the company AGTC. The Foundation is funding the clinical trials at CHOP and Moorfields, and funded much of the preclinical work that made them all possible.

All of the gene therapies in these clinical trials use a manmade adeno-associated virus, or AAV, to deliver normal copies of the RPE65 gene to replace the mutated copies in the retina. More than 40 people have been treated in the five RPE65 gene therapy clinical trials.

For additional information about this study, also see Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations, published in the Archives of Ophthalmology, September 12, 2011.

Gene Therapy in Ophthalmology Update 7: 2012 the Year for Gene Therapy?

While I have previously written about the progress being made in the use of stem cells in ophthalmology (see Stem Cell Update 13) and described the 9-10 clinical trials currently underway or about to start (see Stem Cell Update 14), recent events point to 2012 becoming a breakthrough year for the use of gene therapy to overcome genetic defects that cause several ophthalmic diseases.

In the accompanying table, I list the fourteen clinical trials that I know about in the use of gene therapy in treating ophthalmic disease. Half of the trials are aimed at treating Leber’s Congenital Amaurosis (LCA), while three are for treating the wet form of AMD; one is underway for treating Choroideremia; one for Stargardt’s Disease; and two are aimed at different forms of retinitis pigmentosa (Autosomal Recessive RP and Usher Syndrome 1b).

In addition, I show at least twenty four clinical trials in either the pre-clinical (animal study) mode, or a couple in the IND-preparation mode. That is close to forty clinical trials using gene therapy to treat ophthalmic diseases.

The treatment of Leber’s using gene therapy has been ongoing for at least three years and, as I will show in the next update (Gene Therapy Update 8), those trials are going quite well, with many of the patients showing improved vision.

Finally, as another indicator that gene therapy will play an important role in ophthalmology in this year, Ocular Surgery News is about to begin a special section, OSN Retina, to be part of it’s coverage of the ophthalmic scene. The January 25 issue of Ocular Surgery News will include OSN Retina - a leading destination that will provide retina specialists with more relevant information specific to their field.. The premiere issue will include a feature on how  “Retinal gene therapy may pave the way for attempts to reverse genetic disease: Advancements in retinal gene therapy have prompted a collaborative effort to attain FDA approval.”

For those of you who wish a better understanding of how gene therapy works, and until I write the Primer on the Use of Gene Therapy in Ophthalmology, which I have threatened to write for the past year and a half, you can gain an understanding by reading my first article about gene therapy, written back in November 2010, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD by Retrosense.

Here then is my latest version of Gene Therapy in Ophthalmology by Application:

A pdf file of the table is available by email request.

Stem Cells in Ophthalmology Update 14: Current Stem Cell Clinical Trials

Thanks to new friend, Alexey Bersenev, and his stem cell blog, Hematopoiesis, I have been able to add several companies and medical institutions to my list of those involved in ophthalmic clinical trials using stem cells. Alexey recently posted a blog entry, Cell therapy clinical trials in 2011, describing his efforts to put together a list of entities undertaking stem cell clinical trials. He came up with a total of 151 clinical trials underway, of which eight were in ophthalmology.

I am able to add one that he missed, giving a total of nine clinical trials underway (and another about to start). The new list, showing the trials by ophthalmic application, are presented in the accompanying table.

Anyone wishing a pdf file of the table can get it by sending me an email request.

Stem Cells in Ophthalmology Update 13: Advanced Cell Technology Update

In the wake of the 60 Minutes expose of illegitimate stem cell activities, I thought I would bring you good news about a couple of  legitimate, government approved clinical trials using stem cells.

As part of the Biotech Showcase 2012 conference program, being held in San Francisco, ACT company chairman and CEO, Gary Rabin will present talks on his company’s progress as part of two panels at the Regenerative Medicine State of the Industry Briefing. In advance of his two talks, the company released a statement about the ongoing clinical trials, results and timing, on his From the Chairman company blog.

In his statement, reproduced below, Rabin commented on the progress of two of the three government approved clinical trials currently underway at UCLA’s Jules Stein Eye Institute on treating Stargardt’s Macular Dystrophy and the dry form of age-related macular degeneration (Dry AMD). (See Update 8 and Update 9 for additional information.) (The other clinical trial, also for treating Stargardt’s, is taking place in the UK at Moorfields Eye Hospital in London.[Update 10])

As I reported last July, in Update 9, the first two patients in each of the UCLA trials were treated on July 12th. Since these are safety studies, the investigators are carefully watching the first patients response to the treatment before treating other patients in the twelve patient trials.

Rabin stated, “As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.” (Emphasis added by editor.)

Rabin went on to say, “I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.”

As for publishing the results of the studies, he said that the company would take the appropriate approach of “publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months.”

So, this is good news for the cell stem treatment of retinal diseases.

I have also just learned about several other clinical studies now underway in this field and will discuss them in a followup report (Update 14) to be published either later today or early tomorrow.

Now, here is the complete statement from Mr. Rabin, as taken from his company’s website:

January 10, 2012

Clinical Trials, Results, and Timing

Greetings,

For many of us, the New Year is a time not just for looking forward but for reflecting on events, achievements and lessons learned over the past year. I anticipate an amazing year ahead for ACT, and at the same time I also cannot help but reflect with pride on how far the company has come with its clinical programs over the past year.

IND Filing and Clinical Trials

I will never forget the moment I learned that the company's Investigational New Drug Application (IND) for its human clinical trial for Stargardt's Macular Dystrophy (SMD) had been approved by the FDA. It was clear then that ACT truly was on the road to potentially making medical history. So much has happened in the interim that it is hard to believe that happened only a bit over one year ago, in late November, 2010!

Shortly after that, our IND for Dry Age Related Macular Degeneration (Dry AMD) was also approved. The brief time since then has been a whirlwind of activity in preparation for the clinical trials, and we were enormously pleased and proud to start them in July, at the first site, UCLA's Jules Stein Eye Institute (JSEI).

As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.

Part of what makes research and development in the regenerative medicine sector so exciting is that it involves sailing into largely uncharted waters. ACT's two trials are the only ongoing human embryonic stem cell-based trials, period. We are quite literally creating a new area of medicine. This means there is tremendous pressure on us to "get it right." The responsibility to provide the first-ever validation for this enormously promising new sector rests entirely on our shoulders.

I hope, then, that our many fans and followers can understand why this process takes some time. All eyes are on us, both from the standpoint of support and scrutiny. Should our trials succeed, it could provide the validation that the regenerative medicine sector has been in need of for some time. This is why, in every stage, we are bending over backwards to make sure we cross all our t's and dot all our i's. As the saying goes, Rome wasn't built in a day. If we can successfully complete these trials and bring these therapies to market, though, the potential benefits would be manifold:

*  The potential to at least partially restore sight to millions of people suffering from Dry AMD, the most common cause of blindness for people over age 55.

*  Provide a much-needed validation to the entire regenerative medicine sector.

*  Provide an enormously useful base of scientific knowledge on which we and others can develop other treatments and cures.

*  Last but not least, reward our investors for their patience and support with a return on their investment as befits a company with the only approved treatment for Dry AMD, which has a potential market size of $25-30 Billion in the US and Europe alone, as well as for SMD.

For many years, I was an equity market investment manager. That is an industry where you can evaluate results on a daily basis. Just because you can do that, though, does not mean that you should. The best investors, by far, look at long-term investment opportunities. Running a biotech company is not the same. I am well aware that we have many shareholders who want to know why we don't just treat patients and release results as fast we can, and as fast as available. To do so would be beyond foolhardy for a company like ACT. If there is anything this industry has had some issues with, it is credibility in the mainstream healthcare world. We plan to change that. But to do that, it can't happen overnight. Patient selection, clinical site selection, the timing of patient treatment, and unexpected non-ocular conditions of patients found in health screenings are among the major factors that impact patient treatment. Another factor in the timing of treating these new patients is that we will have at our disposal a new kind of three-dimensional retinal imaging technique, which has not previously been available. Believe me, the timing of patient surgeries has nothing to do with safety, efficacy or availability of suitable patients.

I know that many investors want us to go as fast as possible in treating patients. But there is a tortoise/hare effect here that I simply won't discuss now. I know that it is hard to be patient, but we are making every decision for the best interest of the company in the long run. We don't get bonus points for finishing the trial a few months earlier as compared to making it a truly game-changing medical opportunity. I know that many of you don't know me from Adam, but I'm a very methodical person. Look who we recently added to the Board - one of the leading scientists in the world; one of the best entrepreneurs in the world (founder of Life Alert and eFax), and the CFO of a highly-regarded biotech company considered to have made excellent, value-preserving large bio/pharma partnering deals. We have this under control.

One ill-conceived decision could set the company on a downward path (ACT has been there). Highly prestigious peer-reviewed medical journals do substantial review and due diligence. Top-rated eye hospitals and surgeons are very process-oriented and sometimes bureaucratic. Pushing them harder to move faster doesn't earn you any credibility or success.

Nevertheless, I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.

Publishing Data

The question that inevitably comes up asks when we are going to publish the initial data from the trials. We are eagerly anticipating doing so but we are not going to just post it in raw form. This trial has the potential to make medical history and we want to share the initial results with the world in a strategic way.

The only appropriate approach with data this significant is publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months. We are coordinating the scientific publication with a general mainstream media release strategy (see below). When the paper is published, rest assured that we plan to leverage it to make sure it is very broadly known, not only in medicine, but in the broader medical and scientific community, as well as the investment community.

We sincerely appreciate everyone's patience as we continue this process. We are keenly aware that our investors, fans and other followers are anxious to see the data.

Thank you for your patience and thank you, as always, for your interest and support.

Gary Rabin

Chairman and CEO

Advanced Cell Technology, Inc.

Gene Therapy in Ophthalmology Update 6: First-Ever Clinical Trial for the Autosomal Recessive Form of Retinitis Pigmentosa (arRP) is Underway

It has been difficult keeping up with the changing world of gene therapy in ophthalmology, but thanks to the Foundation Fighting Blindness, I learned yesterday about this new, and first clinical study for treating a rare form of retinitis pigmentosa, underway in Saudi Arabia.

Here is the story, as reported by the FFB’s website:


First Gene Therapy Clinical Trial for Recessive RP is Underway

December 22, 2011 - The field of gene therapy for retinal degenerative diseases is taking a big step forward with the launch of the first-ever clinical trial for people with an autosomal recessive form of retinitis pigmentosa (arRP). The human study, underway at King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, is evaluating gene replacement for individuals with mutations in the gene MERTK, which is a frequent cause of arRP in people of Middle Eastern descent.

While the primary goal of the six-participant, Phase I trial is to evaluate the treatment's safety, investigators will also be looking at its effect on vision.

The treatment works by using a manmade adeno-associated virus, or AAV, to deliver healthy copies of the MERTK gene to cells in the retina. The treatment is contained in a tiny drop of liquid that is injected underneath the retina and absorbed by a layer of cells called the retinal pigment epithelium (RPE).

The MERTK gene plays an important role in the daily maintenance and regeneration of photoreceptors, the retinal cells that enable people to see. During sleep, the tips of photoreceptors are shed and disposed of by the RPE through a process called phagocytosis. Subsequently, the tips grow back. However, when the MERTK gene is defective, the disposal and regeneration process doesn't work properly, and debris and waste products accumulate, causing photoreceptor death and vision loss

"It is great to see clinical trials of gene therapy expanding into more forms of retinal disease and targeting additional mechanisms of disease such as defects in phagocytosis," says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "If successful, it broadens the range of retinal conditions that are amenable to gene therapy."

Dr. Rose notes that, for years, the Foundation has funded several MERTK and phagocytosis research projects, which helped make the current study possible. In addition, the AAV being used for gene delivery is similar to the one used in clinical trials of gene therapy that have restored vision in children and young adults virtually blind from Leber congenital amaurosis.

The MERTK gene therapy trial is being led by Drs. Kang Zhang of the University of California, San Diego, and Fowzan Alkuraya of King Khaled Eye Specialist Hospital. Dr. William Hauswirth, a Foundation-funded gene therapy development expert from the University of Florida, is also on the study team. His lab developed the AAV used in the trial and carried out preclinical safety studies to gain approval for the trial in Saudi Arabia.


Editor’s Note: I have been trying to keep track of the many pre-clinical and clinical studies underway in this ever changing field. I have put together a table of all of the activities underway that I have been able to identify and offer it to all interested parties. Gene Therapy Companies/Institutions Active in Ophthalmology, Version 8, updated as of yesterday, is available in a Word version to any that request it. Use the Email Me! link shown in the right-hand column.

Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

Here is another overview of a presentation made during the Retina SubSpecialty Day Meeting. 

Dr. Elias Reichel, of Tufts University School of Medicine and a founder of Hemera Biosciences, Inc., of Boston, MA, presented on a new approach to treating the dry form of age-related macula degeneration. His paper was based on the research being done by Hemera Biosciences on HMR59, a naturally occurring protein that protects retinal cells from damage by MAC (Membrane Attack Complex), that can be delivered for long-lasting activity via a gene therapy approach. 

HMR59 was developed at Tufts University and subsequently licensed to Hermera Biosciences.  

Complement Regulation via Gene Therapy for Dry AMD 

Elias Reichel, M.D., Professor of Ophthalmology, Tufts University School of Medicine, Boston, MA

HMR59 is a novel therapy primarily targeted at geographic atrophy and other forms of dry age related macular degeneration (Dry AMD) by blocking the final stage of the complement cascade, membrane attack complex (MAC). The complement cascade is implicated via genetic studies as playing a critical role in both wet and dry AMD. 

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. 

HMR59 will be injected directly into the vitreous cavity in an office setting. Such a procedure is currently performed by all retinal specialists using other medications quite commonly. Using the gene therapy approach offers the opportunity to reduce the number of injections needed over a patient's lifetime as the ocular cells will act as factories to produce sCD59, thus addressing the issue of drug delivery. 

 

In summary: 

• The complement pathway is strongly associated with AMD 

• Membrane attack complex (MAC) is the final step in the complement pathway 

• CD59, a naturally occurring protein, protects retinal cells from damage by MAC 

• Hemera Biosciences has developed a gene therapy which produces soluble CD59 (sCD59) that blocks MAC 

• A single intravitreal injection allows for long term protection from AMD progression 

Hemera Biosciences is currently seeking funding to begin animal toxicology studies to get to a phase 1 study in humans. 

Inquiries for further information should be made to: Elias Reichel, MD. 

Gene Therapy in Ophthalmology Update 4: Table of Companies and Institutions Participating

As a followup to the stem cells in ophthalmology table recently published, here is one tabulating the participants using gene therapy in ophthalmology.

When I first wrote about gene therapy in ophthalmology (Gene Therapy for RP and Dry AMD) in November 2010, I began collecting information about the various participants with the thought of writing a Primer, similar to the one I did on stem cells in ophthalmology. At that time, I was able to identify seven companies participating. Since then, and with the help of a few friends, I have now identified nearly thirty companies and institutions using gene therapy approaches to treat ophthalmic diseases. Since I believe access to knowledge is very important, here is the latest version of my table of companies and institutions using gene therapy approaches for treating ophthalmic diseases.

Please let me know of any corrections or omissions.

(An easier to read pdf file of this table is available from the author via email request.)

Stem Cells in Ophthalmology Update 12: Updated Table of Company Participants

When I first wrote about stem cells in ophthalmology (Primer) in September 2010, I was able to identify six companies participating. Since then, and with the help of a few friends, I can now identify eleven companies using stem cells to treat ophthalmic diseases. Since I believe access to knowledge is very important, here is my revised table of companies using stem cells in treating ophthalmic diseases.

Please let me know of any corrections or omissions.

(An easier to read pdf file of this table is available from the author via email request.)

Iluvien Update 4: FDA Turns Down Alimera’s NDA for Approval of Iluvien Again

Alimera again received bad news from the FDA on its application for approval of Iluvien. In a letter (a CRL or complete response letter), the FDA said that questions remained based on the data previously submitted, about the adverse reactions shown by Iluvien in the FAME Study (risk of cataracts and raised IOPs) and that these were not offset by the benefits demonstrated.

The FDA indicated that Alimera would need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

Here is Alimera’s complete new release:


Alimera Sciences Receives Complete Response Letter From FDA for ILUVIEN(R)
Conference Call Scheduled for Monday, November 14 at 8 a.m. Eastern Time

ATLANTA, Nov 11, 2011 (GlobeNewswire via COMTEX) -- Alimera Sciences, Inc., ("Alimera"), a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, today announced that it has received a complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) in response to the New Drug Application (NDA) for ILUVIEN(R) for the treatment of diabetic macular edema (DME) associated with diabetic retinopathy.

A CRL is issued by the FDA's Center for Drug Evaluation and Research when their review of an application is completed and questions remain that precludes the approval of the NDA in its current form.

The FDA stated that it was unable to approve the ILUVIEN NDA because the NDA did not provide sufficient data to support that ILUVIEN is safe and effective in the treatment of patients with DME. The FDA stated that the risks of adverse reactions shown for ILUVIEN in the FAME(R) Study were significant and were not offset by the benefits demonstrated by ILUVIEN in these clinical trials. The FDA has indicated that Alimera will need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

The Company will be requesting a meeting with the FDA to clarify next steps.

ILUVIEN is Alimera's investigational, sustained drug delivery system that releases sub-microgram levels of fluocinolone acetonide (FAc) for the treatment of DME. In December 2010, the FDA issued a CRL to Alimera related to its June 2010 NDA for ILUVIEN, which included data through month 24 of the FAME(TM) Study. In that first CRL, the FDA asked for, among other things, analyses of the safety and efficacy data through month 36 of the FAME Study. Alimera submitted a response to the FDA on May 12, 2011, addressing the issues raised in the first CRL and including 36-month trial data. The FDA classified Alimera's response as a Class 2 resubmission, resulting in a six-month review period and a Prescription Drug User Fee Act, or PDUFA, date of November 12, 2011.

"We are surprised and disappointed with the FDA's decision on our application to market ILUVIEN in the U.S. to patients with this devastating disease. Based on extensive research with U.S. retinal physicians, we have learned that ILUVIEN's long-term sustained delivery treatment benefit is desired and that ILUVIEN has a manageable risk to benefit ratio. We continue to believe in ILUVIEN as a long-term effective treatment option for DME. We are committed to, and have the funds for, pursuing approval in Europe and for evaluating our options in the U.S.," said Dan Myers, president and chief executive officer of Alimera.

For Europe, Alimera expects to submit its formal response to the Preliminary Assessment Report to the Medicines and Healthcare products Regulatory Agency (MHRA) later this month. Based on this submission, the MHRA is expected to make a recommendation on the approvability of ILUVIEN to Alimera and the Concerned Member States (Austria, France, Germany, Italy, Portugal and Spain) by the end of this year, with a decision regarding the approval of ILUVIEN expected in the first half of 2012. The market opportunity in Europe is similar in size to the U.S. market opportunity.

Fighting Retinal Disease: The Promise of New Approaches

Dr. Stephen Rose, the Chief Research Officer of the Foundation Fighting Blindness has just written an article about emerging treatments for retinal diseases, including the use of stem cells, gene therapy and new pharmaceutical approaches. I feel it is important for those of you on the front lines fighting these diseases and those of you who have them, to know that we are getting closer and closer to solving some of the questions about saving sight, and perhaps even bringing back lost sight.

Please take a look at Dr. Rose’s words and dig deeper into the resources available on the FFB website. (I have not included the links that were included with some of his remarks, but you can go to the original on the web and check them out for yourselves.)


What Emerging Treatment Will Work Best for Me?

Written by Stephen Rose, Ph.D., Chief Research Officer, Foundation Fighting Blindness

November 8, 2011 - Hope has never run higher in the fight against retinal degenerative diseases, thanks to clinical trials now underway for gene, stem cell and pharmaceutical therapies. As a result, people affected by these vision-robbing conditions are naturally eager to figure out what emerging treatment approach is going to work best for them.

While it is tempting for someone affected to focus on a "magic bullet" to stop or reverse their disease, I strongly encourage people to consider the Foundation's comprehensive portfolio of emerging treatments when thinking about the future of their vision. Here are three important reasons why:

We can't predict how future research will unfold

Science always has surprises. As an example, until a year or two ago, we believed that corrective gene therapy would be suitable only for treating early-stage disease when a person had a lot of photoreceptors left to save. But recently, Foundation-funded researchers from the University of California, Berkeley and other groups are using gene therapy to enable ganglion cells -- cells in the retina that survive long after photoreceptors are lost -- to provide vision. This research advance has now put gene therapy on the map for potentially reversing total blindness. Previously, we thought that only stem cells or artificial retinas could restore vision in advanced disease.

We need to have back-up plans

In the next couple of years, as we see a big increase in the number of clinical trials for inherited retinal diseases, some setbacks will be inevitable. We need to keep in mind that clinical trials are experiments and, invariably, will not always achieve optimal results. It is critical that we have multiple treatments available, or in the pipeline, for each disease, in case a promising course of action does not pan out. This is one reason pharmaceutical therapies are so important. Generally speaking, they can treat a broader range of conditions than, for example, a gene therapy directed at a specific genetic defect. I envision pharmaceuticals often serving as bridges, or as alternatives, to more targeted therapies. 

Treatment decisions will be personal

Several factors will play a role in determining which treatments might work best for an individual, including his or her genetic profile, stage of disease, age and even tolerance for risk. Let's say in the future that a middle-aged person with retinitis pigmentosa has been taking a drug for many years that's done a good job preserving vision, and along comes a new gene or stem cell therapy. Does that person try a new treatment or stick with what is known to work? There is no right or wrong course of action. What's important is that we fund a diversified portfolio of research, so patients have options. Multiple treatment alternatives may seem like a luxury now, but we are working hard to make that day a reality as soon as possible.

Find out more about Foundation research

The Foundation currently funds 130 grants at 73 institutions around the world. Grants are selected through a rigorous review process conducted by the Foundation's Scientific Advisory Board, which is comprised of the world's top retinal researchers. A complete list of the Foundation's grants is at: www.FightBlindness.org/grants.

Gene Therapy in Ophthalmology Update 3: Genetic Testing of RP Patients Necessary in Order to Direct Treatment

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations
Here is another of the presentations made during the Retina SubSpecialty Day Meeting.

Dr. Stephen Tsang presented on factors and the genetics of retinitis pigmentosa. His paper was based on the article previously published by he and his co-author, Kyle Wolpert, that appeared in the November 2010 issue of Retinal Physician.

The Genetics of Retinitis Pigmentosa
Knowing how the varieties of RP are transmitted can be half the battle of treatment.
Stephen H. Tsang, MD, PhD and Kyle Wolpert, BA

Published in Retinal Physician, November 2010
(Reprinted with permission of the authors)

Retinitis pigmentosa (RP) is a heterogeneous group of diseases characterized by progressive rod-cone dysfunction. Patients initially present with nyctalopia from rod photoreceptor loss, progress to tunnel vision and ultimately experience central vision loss. RP is also the most common form of inherited retinal degeneration, affecting one in 3,000 people.(1,2)

GENETICS BASICS

As a genetically heterogeneous set of disorders, the specific mutation involved in any given case of RP dictates the inheritance pattern and strongly influences the prognosis. As such, a careful family history is essential both for diagnosis and genetic counseling. When possible, the family members of a new RP patient should be examined in order to better define the inheritance pattern. Often, family members may be younger than the age at which the disease develops, which can make this process difficult.

Electroretinogram (ERG) testing, which provides a global assessment of rod and cone function, can measure electro-physiological disturbances long before photoreceptor loss occurs or changes can be seen on fundus examination.(1,3) Thus, ERG testing can help determine whether younger family members will present with the disease later in life, which is useful both for the construction of a pedigree and also for counseling purposes; for example, ERG screening may help a young patient identify plausible career paths.

Described inheritance patterns of RP include autosomal dominant (15% to 35% of cases), autosomal recessive (60%), X-linked recessive (5% to 18%), and mitochondrial. If no other family members are affected, the disease is likely the result of an autosomal recessive (AR) mutation. If the disease presents only in men and is transmitted maternally, then it is likely an X-linked recessive (XLR) mutation. Unlike the recessive modes of inheritance, autosomal dominant (AD) transmission is marked by disease occurrence in every generation and father-to-son transmission.

The rarest form of inheritance is X-linked dominance. These patients are almost always women, as such traits are generally lethal in men. It is possible that a sporadic case could represent a new autosomal dominant mutation, but this is rare. However, the possibility underscores the need for genetic testing to ensure an accurate diagnosis. Mitochondrial mutations are passed maternally and often present systemic problems. Identifying the inheritance pattern involved can help to determine the prognosis, both for the patient and the rest of his or her family.

AUTOSOMAL DOMINANT

Between 15% and 35% of all cases of RP follow an autosomal dominant inheritance pattern.(4,5) As stated previously, AD inheritance is marked by occurrence in each generation and father-to-son transmission of the disease. Compared to AR forms, the AD forms of the disease tend to be more mild, progress more slowly, and present later in life. Patients present with reduced visual acuity and loss of color vision in late adulthood and progress to legal blindness. In the first two decades of life, patients with autosomal dominant RP may be funduscopically indistinguishable from healthy patients. Mutations in rhodopsin, the visual pigment, are responsible for 30% of AD forms of RP. In patients with RP, autofluorescence imaging often shows a characteristic ring of hyperautofluorescence before abnormalities appear on fundus examination; as such, autofluorescence imaging can help to provide presymptomatic clinical evaluation of the patient and predict the course of the disease.(6-8)

Genetic counseling for patients with AD RP is relatively straightforward. Assuming that only one of the patient's parents is affected, each of the patient's children will have a 50% chance of inheriting the mutant allele and thus the disease. Furthermore, an affected patient's siblings each have a 50% chance of being affected. Siblings and children that do not have the allele (as determined by ERG testing) will not pass the disease on to their own children.

AUTOSOMAL RECESSIVE

Autosomal recessive forms of retinal degeneration tend to be more severe, progress more rapidly, and present earlier than the AD forms. As stated previously, the AR inheritance pattern is characterized by sporadic appearance and occurrence in both men and women.

Genetic counseling for patients with AR retinitis pigmentosa is more complicated than for the AD forms. If a patient is affected with an AR form of RP, then both of their parents must have been heterozygous carriers. This means that each of their siblings has a 25% chance of developing the disease and a 50% chance that they are asymptomatic carriers; thus, if a sibling does not have the disease, then there is still a 66% chance that they are carriers. The patient's children will not develop the disease, but each will be a heterozygous carrier, so it may reappear in later generations.

X-LINKED RECESSIVE

The X-linked recessive form of retinal degeneration is often the most severe. It has an early onset, with teenage men showing rod degeneration followed by cone degeneration. Female heterozygous carriers can show patchy areas of rod degeneration due to X-chromosome inactivation, and they present with a metallic, tapeto-like sheen apparent both in autofluorescent and color photographs.(9) The ERG in such carriers is typically affected by age 60.

Genetic counseling for those affected is nuanced due to the nature of the sex chromosomes. Sisters of affected men have a 50% chance of being heterozygous carriers, but they will not develop the disease. Brothers of affected men have a 50% chance of developing the disease, but if they do not, then they will not be heterozygous carriers. Sons of affected men will not be affected. Daughters will be heterozygous carriers, and as such, their own children will have a 50% chance of receiving the mutant allele.

GENETIC TESTING

It is essential that patients with retinitis pigmentosa submit to genetic testing, both for purposes of prognosis and for the improved understanding of the genetics of RP. There are 15 genes known to be associated with autosomal dominant RP, 17 genes associated with autosomal recessive RP, and two genes associated with X-linked RP.

There is currently a 30% chance that blood submitted for genetic testing will be matched with a known mutation within one year of submission. Knowing the inheritance pattern before submitting blood for genetic testing is important because there are different gene chips used when testing for RP genes: one with dominant mutations and one with recessive mutations.(10) This helps to streamline the process by avoiding the need for extraneous testing, making it more cost efficient.

Genetic tests can cost the patient hundreds of dollars, so reducing the price by narrowing the scope of the test is important. Genetic testing of all patients is important because the genotype-phenotype correlation can vary such that different members of a family express the disease differently or, alternatively, that different mutations manifest similar fundus alterations.(8)

Genetic testing for mitochondrial mutations is much more complicated than standard testing. In genetic testing of normal DNA, a blood sample is taken and submitted for testing, but mitochondrial testing requires a biopsy of the retina itself.

GENE THERAPY

For many years, cures for RP have been largely unavailable. However, recent developments point to the promise that, in some cases, gene therapy could arrest the progression of RP and perhaps even restore lost vision. Gene therapy can be difficult in most organ systems because the body's immune response causes a rejection of the introduced material. However, the eye is a rather immunoprivileged site, and as such, gene delivery using adeno-associated virus has been shown to be effective.

Several studies published in 2008 demonstrated the efficacy of gene therapy to help patients with an early-onset autosomal recessive form of retinal dystrophy, known as Leber's congenital amaurosis.(11-13) Gene therapy success can be measured noninvasively through the use of techniques such as ERG testing and autofluorescence imaging.

One major impediment to the development of gene therapies is that they are gene specific. This is why it is crucial that the database of known mutations be expanded. The inheritance pattern of a given mutation is also important for determining the relative likelihood of the development of successful gene therapies. Recessive genes are relatively easy to treat with "gene-replacement" therapy because the eye simply lacks a functional copy of the gene; if a functional copy is introduced, then results can be seen. Dominant genes are more complicated because they require "gene correction" in order to essentially override the deleterious effects of the mutant allele.

Cell replacement therapy using induced pluripotent stem cells is another treatment currently in development that may be an effective treatment for both AD and AR forms of RP.(14) Mitochondrial gene therapy is not currently a realistic possibility. However, stem-cell therapy has worked as a temporary treatment for the bone marrow in Pearson syndrome, so similar stem-cell therapy may someday be available for the retinal atrophy resulting from mitochondrial disorders.

SUMMARY

More treatments for retinitis pigmentosa are foreseeable in the coming decade, but genetic testing of RP patients is essential in order both to understand better the genetic associations of the disease and to direct efforts at developing treatments. However, even before implementing genetic testing, it is important to obtain, as much as possible, a complete family history in order to identify the inheritance pattern of the disease. The inheritance pattern has serious implications for the prognosis of the patient and is critical for genetic counseling for the patient and his or her family. RP




REFERENCES

1. Humphries P, Kenna P, Farrar J. On the molecular genetics of retinitis pigmentosa. Science. 1992;256:804-808.
2. McKusick VA, Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol CD-ROM. 12th ed. Baltimore, MD; The Johns Hopkins University Press; 1998.
3. Berson EL, Gouras P, Hoff M. Temporal aspects of the electroretinogram. Arch. Opthalmol. 1969;81:207-214.
4. Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J of Opthalmol. 1984;97:357-365.
5. Ayuso C, Garcia-Sandoval B, Najera C, Valverde D, Carballo M, Antinolo G. Retinitis pigmentosa in Spain. The Spanish Multicentric and Multidisciplinary Group for Research into Retinitis Pigmentosa. Clin Genet. 1995;48:120-122.
6. Lima LH, Cella W, Greenstein VC, et al. Structural assessment of hyperautofluorescent ring in patients with retinitis pigmentosa. Retina. 2009; 29:1025-1031.
7. Tsang SH, Vaclavik V, Bird AC, Robson AG, Holder GE. Novel phenotypic and genotypic findings in X-linked retinoschisis. Arch Ophthalmol. 2007; 125:259-267.
8. Tsui I, Chou CL, Palmer N, Lin CS, Tsang SH. Phenotype-genotype correlations in autosomal dominant retinitis pigmentosa caused by RHO, D190N. Curr Eye Res. 2008;33:1014-1022.
9. Zeiss CJ, Ray K, Acland GM, Aguirre GD. Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3). Hum Mol Genet. 2000;9:531-537.
10. Tsang SH, Tsui I, Chou CL, et al. A novel mutation and phenotypes in phosphodiesterase 6 deficiency. Am J Ophthalmol. 2008;146:780-788.
11. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358:2231-2239.
12. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240-2248.
13. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008;105:15112-15117.
14. Gouras P, Kong J, Tsang SH. Retinal degeneration and RPE transplantation in Rpe65(-/-) mice. Invest Ophthalmol Vis Sci. Oct 2002;43:3307-3311.

Stephen H. Tsang, MD, PhD, is an ophthalmic geneticist and ERG attending at Columbia. Kyle Wolpert, BA, is a laboratory assistant at the Harkness Eye Institute of the Columbia University Medical Center. Neither author reports any financial interest in any products mentioned in this article. Dr. Tsang can be reached via e-mail at dr.stemcells@gmail.com.

Gene Therapy in Ophthalmology Update 2: Foundation Fighting Blindness Funds Six New Gene Therapy Projects

In a news release that I found on the net, I learned that the FFB was going to put $8.25 million into six gene therapy projects, either already underway or about to start. The release contains good information about several projects that I knew about, and others that I did not.

Here, for your edification is their news release:


Foundation Fighting Blindness Invests $8.25 Million in 6 New Gene Therapy Research Projects
Foundation Fighting Blindness, 10/25/11

The Foundation Fighting Blindness, a national nonprofit dedicated to advancing sight-saving research, announces an $8.25 million investment in six new gene therapy research projects that are targeted to have treatments ready for clinical trials within three years. The grants focus on treating a broad range of retinal degenerative diseases and will be allocated through the Foundation's Translational Research Acceleration Program, which funds research efforts with strong, near-term clinical potential.

"The Foundation Fighting Blindness recognizes the great potential of gene therapy for saving and restoring vision, and we're eager to build on the clinical development of retinal gene therapies that has been accelerating at an incredible rate over the past few years," said Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "It was just three years ago that we reported groundbreaking results from our first gene therapy clinical trials that restored vision in children and young adults who were virtually blind from Leber congenital amaurosis (LCA). The success of those studies set the stage for this rapid expansion in gene therapy development."

As part of the new $8.25 million investment, one innovative project involves the use of gene therapy to resurrect and reactivate cone cells that are compromised by disease. In many inherited retinal conditions, including retinitis pigmentosa, cones stop working before they completely degenerate. The Institut de la Vision in Paris and the Friedrich Miescher Institute in Basel, Switzerland, are developing a gene therapy that revives degenerating cones, enabling them to regain their ability to respond to light and provide vision. The treatment also improves the health of cones and extends their lifespan significantly. This therapeutic approach holds the potential to benefit people affected by a range of conditions, because it works independently of the underlying disease-causing genetic defect. Resurrecting cones can improve an affected individual's well being, because these cells provide central, daytime and detailed vision that is critical for independent living.

The Foundation is also funding the Oklahoma University Health Sciences Center, which in collaboration with Copernicus Therapeutics, is developing a nanoparticle gene therapy system.
Nanoparticles are tiny manmade particles, 1/12,000th the diameter of a human hair, which can readily penetrate retinal cells, making them effective for delivery of therapeutic genes. They may provide advantages in certain cases over viral gene delivery technologies currently used in retinal disease therapies. Perhaps most beneficial is their ability to deliver large genes - genes that exceed the capacity of viral delivery systems - for treating some diseases.

Through a Foundation grant to Applied Genetic Technologies Corp. (AGTC), a clinical stage biotechnology company, funds will support researchers at Oregon Health & Science University's Casey Eye Institute and the University of Florida in their pre-clinical work to evaluate a gene therapy treatment for X-linked retinoschisis, a blinding disease that affects over 35,000 patients in the United States and Europe.

Portions of the Foundation's $8.25 million investment will also go toward research happening at the Massachusetts Eye and Ear Infirmary and the University of Florida for projects investigating gene therapy for two different LCA-causing genes. The final grant supports work at the University of Pennsylvania for choroideremia gene therapy led by Dr. Jean Bennett, who is also one of the lead investigators on the landmark LCA gene therapy clinical trial that has restored vision in more than 40 patients.

There are now human studies of gene therapy underway for Leber congenital amaurosis, wet age-related macular degeneration, and Stargardt disease, with clinical trials for Usher syndrome (the leading cause of deaf-blindness) type 1B and autosomal recessive retinitis pigmentosa scheduled to begin in late 2011 or early 2012. Currently supporting 30 other gene therapy efforts, including RDH12 and other genetic forms of LCA and RP, which are at various stages of development, the Foundation allocates funding toward basic research and investigation into a gene's role in disease, as well as projects poised for clinical trials.

Editor's Note: I have put together a matrix, that at the moment contains eight companies involved in Gene Therapy in Ophthalmology projects. Anyone wishing to obtain a copy of the matrix, please email me.