Wednesday, October 15, 2014

Stem Cells in Ophthalmology Update 27: ACT Interim Clinical Results Are Outstanding

Having treated 36 patients in two clinical trials for Stargardt’s Macular Dystrophy (SMD - 24 patients to date) and for dry Age-Related Macular Degeneration (AMD - 12 patients to date), Advanced Cell Technology reported the interim results obtained with 18 of these patients (9 in each trial) in the US-based studies. Both trials (NCT01345006 - Stargardt’s, and NCT01344993 - AMD) began in July 2011, giving the company up to three-year’s data for the earliest patients, and a median of 22 months followup for all. The interim results were reported in The Lancet, published online October 14, 2014 in: “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies”.

An additional Stargardt’s trial, being conducted at two clinics in the United Kingdom, with 12 patients enrolled (NCT01469832), along with 3 of the 4 patients treated in each of two trials with better vision candidates, as part of the two clinical trials in the publication (Phase IIa), were not included in The Lancet results.

As noted by Paul K. Wotton, Ph.D., President and Chief Executive Officer of Advanced Cell Technology, "These study results represent an important milestone and strengthen our leadership position in regenerative ophthalmology. We would like to thank the patients for their willingness to participate in these studies. Our findings underscore the potential to repair or replace tissues damaged from diseases. We plan to initiate comprehensive Phase 2 clinical trials for the treatment of both AMD and SMD, two disease states where there is currently no effective treatment."

Editors Note: As announced on October 15th by the company, the Phase II dry AMD clinical trial (50 Patients) will start during the 1st Half of 2015 and is expected to be completed in the middle of 2016, taking place at 10 Trial Sites across North America. The Phase II SMD clinical trial (100 patients) will start during the 4th Quarter of this year or by the end of the year. It will take 18-24 months to complete, taking place at 30 sites across North America and Europe.

Robert Lanza, M.D., Chief Scientific Officer of ACT and co-senior author of the paper, commented, "Diseases affecting the eye are attractive first-in-man applications for this type of investigational therapy due to the immune-privileged nature of the eye. Despite the degenerative nature of these diseases, the vision of 10 of 18 patients showed measurable improvement at the six month follow up, after transplantation of the RPE cells. Furthermore, the cells have been well tolerated for a median period of 22 months with two of the patients treated more than three years ago. We are pleased that there have been no serious safety issues attributable to the cells observed in any of the patients."

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 and co-lead author of the publication said, "The data published in The Lancet support the potential safety and biological activity of stem cell-derived retinal tissue. Once again, surgical access to the subretinal space has proven safe. However, for the first time in humans, terminally differentiated stem cell progeny seem to survive, and do so without safety signals. Combined with the functional signals observed, these data suggest that this regenerative strategy should move forward. This is a hopeful and exciting time for ophthalmology and regenerative medicine."

These two studies provide the first evidence of the mid- to long-term safety, survival, and potential biologic activity of pluripotent stem cell progeny into humans with any disease. In addition to showing no adverse safety issues related to the transplanted tissue, anatomic evidence confirmed successful engraftment of the RPE cells, which included increased pigmentation at the level of the RPE layer after transplantation in 13 of 18 patients.

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. Thirteen (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt’s macular dystrophy.

Figure 3: Change from baseline in best-corrected visual acuity in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B) Median change in best-corrected visual acuity was expressed as number of letters read on the Early Treatment of Diabetic Retinopathy Study visual acuity chart in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B). Red lines show treated eyes and blue lines show untreated eyes of patients during the first year after transplantation of the cells derived from human embryonic stem cells. Green lines show the difference between the treated and untreated eyes. Patients who underwent cataract surgery after transplantation are not included in the graph. There was a significant difference in the letters read in transplanted eyes of patients with age-related macular degeneration versus non-transplanted controls at 12 months (median 14 letters vs –1 letter; p=0·0117). There was an increase in letters read in transplanted eyes of patients with Stargardt’s macular dystrophy versus non-transplanted controls at 12 months (median 12 letters vs two letters, although the sample size was too small to allow reliable calculation of the Wilcoxon signed-rank test).
The SMD and dry AMD trials are prospective, open-label studies designed to evaluate the safety and tolerability of human embryonic stem cell (hESC)-derived RPE cells following sub-retinal transplantation into patients at 12 months, the studies' primary endpoint. Three dose cohorts were treated for each condition in an ascending dosage format (50,000 cells, 100,000 cells, and 150,000 cells). Both the SMD and dry AMD patients had subretinal transplantation of fully-differentiated RPE cells derived from hESCs.

Dr. Anthony Atala, a surgeon and director of the Wake Forest Institute for Regenerative Medicine at Wake Forest University in an accompanying commentary in The Lancet said:

"It really does show for the very first time that patients can, in fact, benefit from the therapy.
That allows you to say, 'OK, now that these cells have been used for patients who have blindness, maybe we can also use these cells for many other conditions as well, including heart disease, lung disease and other medical conditions.' "

Human embryonic stem cells have the ability to become any kind of cell in the body. So scientists have been hoping the cells could be used to treat many diseases, including Alzheimer's, diabetes and paralysis. But the study is the first human embryonic stem cell trial approved by the Food and Drug Administration that has produced any results.

"It is really a very important paper."

The co-authors of the study summarized their interpretation of their results in this way:

“The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that human-embryonic-stem-cell-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.”

My takeaway from reading The Lancet article (and several of the accompanying writeups about the study) is, the use of RPE derived from embryonic stem cells is safe and efficacious, particularly in the eye. But most of all, this important study shows that Advanced Cell Technology is able to safely stop the progression of to-date untreatable dry AMD and SMD retinal diseases (17 of 18 patients) and to improve the vision in those who have lost considerable sight (10 of 18 patients).

Finally, the two clinical trials that are reported on in The Lancet, were done on patients with nothing to lose (with vision no better than 20/400), whereas patients in the Phase IIa study, still in progress, have vision no worse than 20/100. It is anticipated that even better results will be shown with this better vision group.


Other Resources:

Encouraging New Paper on ACT Stem Cell-Based Trial for Macular Degeneration, Paul Knoepfler, Knoepfler Lab Stem Cell Blog, October 14, 2014

Embryonic Stem Cells Restore Vision In Preliminary Human Test, Rob Stein, NPR Health Blog, October 14, 2014

Disclosure: As of September 17, 2014, I own a small number of shares of the company’s stock.

Friday, September 26, 2014

Iluvien Update 8: Alimera Sciences Receives FDA Approval of Iluvien for Treatment of DME

After several attempts to gain approval for its NDA for Ilunien, the FDA has finally seen the light (after approval in the UK, Germany, and marketing or pending approvals in seventeen other EU countries).

I first began writing about Iluvien in July 2010 – see my comprehensive writeup about the technology behind this and other sustained delivery drug systems – Iluvien and the Future of Ophthalmic Drug Delivery Systems. In addition I have written about the products progress in seven updates, the latest in August 2012, Iluvien Update 7: Alimera Sciences to Re-File for FDA Approval of Iluvien for Chronic DME

Here are the statements from the two companies involved in bringing Iluvien to the market, Alimera Sciences, the marketing arm, and pSivida the licensor of the technology to Alimera:

Alimera Sciences announced that the U.S. Food and Drug Administration (FDA) has approved ILUVIEN for the treatment of diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP). Alimera currently intends to begin selling ILUVIEN in the U.S. in the first quarter of 2015.

"We are very excited with this news from the FDA and thank the many people who contributed to this outcome and believed in ILUVIEN, including the retinal specialists, clinical site personnel, reading centers, and the many patients and their caregivers for helping us bring this long-term treatment to people in the U.S. with DME," said Dan Myers, president and chief executive officer of Alimera. "The approval of ILUVIEN under this broader label brings a DME treatment to the U.S. that lasts years, not months, after a single injection and greatly expands the addressable market opportunity in the U.S."

"The approval of ILUVIEN is wonderful news for the retinal community, as recent studies have indicated that as many as 50 percent of DME patients are not optimally managed with today's standard of care known as anti-VEGF therapies," said Pravin Dugel, M.D., Retinal Consultants of Arizona and clinical associate professor, Doheny Eye Institute, Keck School of Medicine, University of Southern California. "Having a multi-year delivery, low-dose corticosteroid drug will provide an additional treatment option for patients with this disease."

ILUVIEN (fluocinolone acetonide intravitreal implant) 0.19 mg is a sustained release intravitreal implant approved in the U.S. to treat diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Each ILUVIEN implant is designed to release submicrogram levels of fluocinolone acetonide (FAc), a corticosteroid, for 36 months. The ILUVIEN approval was based on clinical trial data that showed that at month 24 after receiving the ILUVIEN implant, 28.7 percent of patients (p value .002) experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. Patients treated with ILUVIEN experienced a statistically significant improvement in visual acuity compared to the control group by week three of follow up, and maintained a statistically significant advantage over the control through completion of the trial at month 36.

"As the role of inflammation in DME becomes more clearly understood, the use of a continuous, long-term, low-dose anti-inflammatory, such as ILUVIEN, is an important option for patients who have DME that persists," said Barry Kuppermann, M.D., Ph.D., professor and chief of the Retina Service at University of California, Irvine.

"As the glaucoma specialist on the FAME Study Data Safety Monitoring Board, I have extensive familiarity with the IOP data related to ILUVIEN," said Richard Parrish, M.D., Professor and Director of the Glaucoma Service at the University of Miami Miller School of Medicine, Bascom Palmer Eye Institute.  "I am confident that the benefits of this important treatment for DME will outweigh concerns related to elevated IOP in the indicated patients."

And, from pSivida:

pSivida today announced that the U.S. Food and Drug Administration (FDA) has approved ILUVIENr for the treatment of diabetic macular edema (DME). It is indicated for patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP). A single injection of the ILUVIEN micro-insert provides sustained treatment of DME for 36 months. Approximately 560,000 people in the U.S. are estimated to have clinically significant DME, the most frequent cause of vision loss in individuals with diabetes and the leading cause of blindness in young and middle-aged adults in developed countries. ILUVIEN is expected to be commercially available in the U.S. in early 2015.

FDA approval of ILUVIEN entitles pSivida to a $25 million milestone from its licensee Alimera Sciences. pSivida will also be entitled to 20% of the net profits from sales of ILUVIEN in the U.S.

"FDA approval of ILUVIEN, our third FDA-approved product for retinal disease, provides an important treatment option for DME patients in the U.S., the majority of whose DME, despite anti-VEGF intra-ocular injections as frequently as monthly, is not optimally managed. ILUVIEN's clinical trials showed that ILUVIEN can actually reverse vision loss in many DME patients. Another advantage of ILUVIEN over existing therapies is that a single injection provides sustained therapy for three years," said Paul Ashton, Ph.D., president and chief executive officer of pSivida.

"The $25 million milestone will help finance our ongoing product development program, including MedidurT for posterior uveitis and TethadurT for the sustained delivery of biologics," added Dr. Ashton. pSivida is independently developing Medidur, an injectable, sustained release micro-insert of the same design and delivering the same drug as ILUVIEN, for the treatment of chronic posterior uveitis, the third largest cause of blindness in the U.S. The Company plans to seek FDA approval of this product on the basis of its ongoing single Phase III clinical trial. Enrollment of this study is expected to be completed by the end of the first quarter of calendar 2015.

ILUVIEN is already commercially available in the U.K. and Germany, and has received or is pending marketing approval in seventeen other EU countries, for the treatment of patients with the chronic DME insufficiently responsive to available therapies. "We are very pleased that the FDA's approval of ILUVIEN is not limited, as in the EU, to the subset of patients with chronic DME, patients who have failed other therapies, or patients who have had cataract surgery," continued Dr. Ashton.

ILUVIEN is an injectable micro-insert that provides sustained treatment through continuous delivery of a submicrogram dose of the corticosteroid fluocinolone acetonide for 36 months. Current standard-of-care therapy requires anti-VEGF injections into the eye as frequently as monthly, and studies show that over 50 percent of patients are not optimally managed with this treatment. FDA approval was based on clinical trial data that showed that at month 24, 28.7 percent of patients receiving ILUVIEN experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. This improvement in vision was maintained through 36 months, the end of the trials. 

Monday, September 15, 2014

Retina Revealed

Over the weekend, I read an excellent account of how the various parts of the retina work. Ben Shaberman, the senior science writer for the Eye on the Cure blog (Foundation Fighting Blindness), put together an easy to read and understand overview of what the various cell layers of the retina do and how they interact. Since the retina is the focus of most of what I write about, I asked Ben for his permission to reproduce the writeup in this space. Permission was granted and here is what he wrote:

By Ben Shaberman,  September 8, 2014
Eye on the Cure - Foundation Fighting Blindness

Your eyes are not just windows to your soul, but to your health as well. People rarely pay attention to their eyes, until something goes wrong. The eye is a delicate organ, and vision is a complex process involving various components.

Photoreceptors, in particular, get a lot of attention from researchers because they're the main cells in the retina that make vision possible. They convert light into electrical signals, which are sent to the brain and used to construct the images we see. Also, many retinal diseases begin with loss of photoreceptors.

However, the retina is like a multi-layer cake, with each layer comprised of different types of cells, all playing important roles in retinal health and vision. While preserving and restoring photoreceptors is often job number one for scientists, they also explore ways to protect other retinal cells from deterioration and even harness them to restore vision.

Here's a summary of the major retinal cell types, their functions and their potential roles in future treatments of diseases:

Choroid - The choroid is a layer of blood vessels that supplies oxygen and nourishment to the retina. Defects in the CHM gene cause choroideremia, a disease characterized by deterioration of the choroid, retinal pigment epithelium (RPE) and photoreceptors. In the wet form of age-related macular degeneration, leaky blood vessels expand from the choroid into the retina – a process called choroidal neovascularization – which causes loss of photoreceptors and central vision.

Retinal pigment epithelium - Also known as the RPE, this is a single layer of cells above the photoreceptors that provides them with essential nutrition and waste removal. In age-related macular degeneration (AMD) and Stargardt disease (SMD), toxic waste products accumulate in the RPE or between the RPE and photoreceptors. Subsequently, the RPE deteriorates, leading to loss of photoreceptors.

Photoreceptors -These are the retinal cells, known as rods and cones, that initiate the vision process by converting light into electrical signals. Rods provide low-light and peripheral vision. Cones are concentrated in the macula, the central region of the retina, and provide central and color vision. The outer segments of rods and cones are antenna-like projections that absorb light and convert it into electrical signals. Inner segments are the cell bodies where other supportive functions are performed. The adult human retina has approximately 125 million photoreceptors.

Bipolar cells - Their job is to receive electrical information on lighting intensity from photoreceptors and pass it along to other retinal cells. Bipolar cells often survive after photoreceptors are lost to disease. This makes them an attractive target for emerging optogenetic treatments, which are designed to provide light sensitivity and restore vision.

Ganglion cells - Ganglion cells receive input from many different cells in the inner retinal layers and process visual information, including detection of edges, contrast and colors. Ganglion cells extend to form an optic nerve, a million-fiber cable that conveys visual information from the eye to the brain. In people with advanced retinal disease, ganglion cells often survive longer than bipolar cells, making them a potential target for optogenetic therapies. Currently, scientists believe that bipolar cells may provide a more detailed visual experience than ganglion cells when treated with a light-sensing therapy, because they reside in layers of the retina closer to photoreceptors.

Muller glia - Muller cells extend through the retina, like spokes of a wheel, providing structural support and guiding light through the inner retina. They also transport molecules critical to retinal health and vision. Researchers believe Muller cells may even have the capacity to become new photoreceptors, which could lead to restoring vision. The research is still new, but success might someday have a big impact on the vision of people with advanced diseases.

A final note

The processing of visual information in the retina-beginning with 125 million photoreceptors and converging on a one-million-fiber optic nerve-remains a subject of intense research. There's still much that scientists don't know about the retinal cells and their roles. For example, little is known about the processing activities of amacrine and horizontal cells, which reside between bipolar and ganglion cells. However, advancing imaging technologies, including adaptive optics and optical coherence tomography, are helping complete the picture.

For additional information about retinal anatomy and function, please see the Eye on the Cure post "Appreciating the Beauty of the Retina." The University of Utah's Webvision is one of the best online sources for detailed information about the retina. I also want to thank John Flannery, Ph.D., at the University of California, Berkeley, for his editorial input.

Saturday, September 13, 2014

Stem Cells in Ophthalmology Update 26: First Wet AMD Patient Treated With RPE Derived from iPS Cells

Earlier this week, it was reported that Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe had appeared in front of a 19-member health-ministry committee for the safety of the clinical use of stem cells. She was flanked by Shinya Yamanaka, the biologist who first created iPS cells. Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine for his breakthrough and now heads the Center for iPS Cell Research and Application in Kyoto. Takahashi was seeking approval to implant a retinal pigmented epithelial (RPE) sheet made from induced pluripotent stem (iPS) cells into a human patient.

Takahashi and her collaborators had shown in monkey and mice studies that iPS cells generated from the recipients' own cells did not provoke an immune reaction that causes them to be rejected. There had been concerns that iPS cells could cause tumours, but Takahashi's team found that to be unlikely in mice and monkeys.

To counter further fears that the process of producing iPS cells could cause dangerous mutations, Takahashi's team had performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants. The health ministry said that no problems were found and that the human trial could commence.

Only four days later (Friday, September 12th), the first patient was treated with the implanted sheet of RPE cells. She derived them from the patient's skin cells, after producing induced pluripotent stem (iPS) cells and then getting them to differentiate into retinal cells.

This is a major first for the stem cell and regenerative medicine fields.

Takahashi and her collaborators have been using induced pluripotent stem (iPS) cells to prepare a treatment for age-related macular degeneration. Unlike RPE derived from embryonic stem cells (i.e., as being done by Advanced Cell Technology), iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. The CDB trial will be the first opportunity for the technology to prove its clinical value.

A Japanese woman in her 70s is the world's first recipient of cells derived from induced pluripotent stem cells, a technology that has created great expectations since it could offer the same advantages as embryo-derived cells but without some of the controversial aspects and safety concerns.

In a two-hour procedure starting at 14:20 local time, a team of three eye specialists lead by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells into an eye of the Hyogo prefecture resident, who suffers from age-related macular degeneration.

The procedure took place at the Institute of Biomedical Research and Innovation Hospital, next to the RIKEN Center for Developmental Biology (CDB) where ophthalmologist Masayo Takahashi had developed and tested the epithelium sheets.

Afterwards, the patient experienced no effusive bleeding or other serious problems, as reported by RIKEN.

Another important element to this story is that Japan has a clinical translation pipeline that is now faster with recent changes in regulations than that of the US. For example, this and future iPS cell-based transplants were approved as part of a clinical study, a type of clinical research mechanism that doesn't exist in the US. It is safe to say that the same technology with the same research team and outstanding level of funding would still be at least a few years away from their first patient in the US due to the different regulatory scheme.

As noted by Dr. Paul Knoepfler, in his writeup about the procedure:

 “The patient is clearly a brave hero. The team transplanted a huge (from a bioengineering perspective) 1.3 x 3.0 mm sheet of RPEs into the retina of the patient, who did not have any clear immediate side effects from the procedure. Keep in mind again that this sheet was made indirectly from the patients own skin cells so it is an autologous (or self) transplant, a notion that 10 years ago would have seemed entirely like sci-fi.”

“This is not only a huge milestone, but also an astonishingly fast translation of iPS cell technology from the bench to the bedside.”

 “Also, on the positive side we have the encouraging results from the ongoing clinical trials from Advanced Cell Technology (ACT) using a similar approach to macular degeneration, but employing human embryonic stem cells to make the RPEs.”

“For the vision impaired and the broader stem cell field, it is heartening to have two such capable teams working to cure blindness with pluripotent stem cells.”


3. Stem cell landmark: patient receives first ever iPS cell-based transplant, Knoepfler Lab Stem Cell Blog, Paul Knoepfler, Septermber 12, 2014.

Thursday, August 21, 2014

A Potential New Approach to the Treatment of Retinitis Pigmentosa

In a recently published study (1), researchers at the Columbia University Medical Center (CUMC) have come up with a novel approach in developing an individualized treatment for RP patients, using the patients' own cells transformed into an in vitro model for studying the disease and developing a potential treatment.

While RP can begin during infancy, the first symptoms typically emerge in early adulthood, starting with night blindness. As the disease progresses, affected individuals lose peripheral vision. In later stages, RP destroys photoreceptors in the macula, which is responsible for fine central vision. RP is estimated to affect at least 75,000 people in the United States and 1.5 million worldwide.

Mark Hillen, editor of The Ophthalmologist has written about this new approach, and I have reproduced the writeup, with his permission.

Might you soon take a skin cell from a patient with retinitis pigmentosa, roll it back to a pluripotent state, culture it to become retinal cells and trial gene therapy on it in vitro?

By Mark Hillen
The Ophthalmologist, July/August 2014

Personalized medicine is a particularly hot topic in medicine. Take cells from a patient, modify or grow them, and return them to the patient for their therapeutic effects. What a team of Manhattan-based researchers are doing at the Columbia University Medical Center (CUMC) is something rather special. They take skin epithelial cells from patients with retinitis pigmentosa (RP), turn them into induced pluripotent stem (iPS) cells, then differentiate them into retinal cells in cell culture, enabling them to examine what the structural and functional defects of these retinal cells really are - without having to perform a dangerous (and ethically dubious) excision of a section of a patient's retina to do so (1).

More than 60 different genes have been linked to RP, making it a challenge to go to a mouse model to study the disease. Making a genetically-modified mouse is time consuming enough, but there's the additional confounding factor that the retinae of mice and men have enough interspecies differences to induce a great depression in researchers. This is why the ability to study the patient's own retinal cells in culture is so valuable.

Using this approach, the CUMC researchers examined cells from a patient with RP that resulted from a mutation in the MFRP (membrane frizzled-related protein) gene. Analysis of these cells showed that the primary effect of MFRP mutation is to disrupt the regulation of the major cytoskeletal protein, actin (Figure 1). "Normally, the cytoskeleton looks like a series of connected hexagons," said lead researcher, Stephen Tsang. "If a cell loses this structure, it loses its ability to function."

In the next phase of the study, the CUMC team used adeno-associated viruses to introduce normal copies of MFRP into the iPS-derived retinal cells (in cell culture), successfully restoring the cells' function. The team went on to successfully use gene therapy to rescue the "normal" phenotype in mice with MFRP mutation-induced RP.

Does this herald a future of personalized medicine, where patients can have their retinae reproduced from skin cells, their disease state assessed, and potential gene therapy options trialled, all in vitro, in order to choose the most effective gene therapeutic option? Tsang believes so, concluding that, "The use of patient-specific cell lines for testing the efficacy of gene therapy to precisely correct a patient's genetic deficiency provides yet another tool for advancing the field of personalized medicine. iPS cells can help us determine whether these genes do, in fact, cause RP, understand their function, and, ultimately, develop personalized treatments."

Figure 1. a. Normal (wild-type) retinal cells: the protein actin forms the cell's cytoskeleton, creating an internal support structure that looks like a series of connected hexagons; b. This structure fails to form in cells with MFRP mutations, compromising cellular function; c. Diseased retinal cells, when treated with gene therapy to insert normal copies of MFRP, have normal-looking cytoskeletal structures and function.


1. Y. Li, W.-H. Wu, C.-W. Hsu, et al., "Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects", Mol. Ther. Epub ahead of print (2014). doi:10.1038/mt.2014.100.

Sunday, May 25, 2014

Menu 21: A List of Writeups on Gene Therapy Used in Ophthalmology

As with my menu on stem cells used in ophthalmology (Menu 20), here is one for the current articles on the use of gene therapy in ophthalmology, with links to the full writeups.

(Updated May 25, 2014)

Gene Thearpy

After several discussions with Sean Ainsworth, the founder of RetroSense, and much online research, I think I have learned a little about what gene therapy is about, and its application in ophthalmology, especially in the possible restoration of vision in those who suffer from retinitis pigmentosa (RP). Thanks to Sean for whetting my appetite -- here is what I have learned.

In an announcement today, Oxford BioMedica said that it had gained approval from the FDA to begin a Phase I/IIa Clinical Trial for a form of Usher’s Syndrome, Type 1B, which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

In a news release that I found on the net, I learned that the Foundation Fighting Blindness 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.

In  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.

Gene Therapy in Ophthalmology Update 4: Table of Companies and Institutions Participating Nov. 2011

Again, this table is currently out-of-date. See Update 16.

A writeup about a start-up company, Hemera Biosciences, with a gene therapy approach to treating dry AMD.

Thanks to my friends at the Foundation Fighting Blindness, I learned about this first human clinical trial using gene therapy for treating recessive retinitis pigmentosa.

In this opus, I discuss my reasons why I think 2012 is going to be the year for gene therapy and also presented my table of current clinical trials underway. (Again, note there is now an updated table available via Update 16.)

A report on the progress being made in treating Leber’s using gene therapy, as reported by the Foundation Fighting Blindness.

Gene Therapy in Ophthalmology Update 9: Oxford BioMedica/OHSU Preparing to Treat First Usher Syndrome Patient & Oxford BioMedica Ophthalmic Program Update Mar. 2012

A report on the start of the program to treat Usher Syndrome patients at OSHU, and an update on other ophthalmic programs underway by Oxford BioMedica.

Gene Therapy in Ophthalmology Update 10: Gene Therapy Research in Dogs Cures X-Linked Retinitis Pigmentosa – Paves the Way for Similar Treatment in Humans  Mar. 2012

Researchers at several universities and laboratories collaborated to treat dogs afflicted with the x-linked form of retinitis pigmentosa, to deliver the therapeutic RPGR gene specifically to the diseased rods and cones, which led to functional and structural recovery. This is the first proof that this condition is treatable in an animal model and the researchers feel the results are promising and relevant for translation to humans afflicted with this disease.

Gene Therapy in Ophthalmology Update 11: Clinical Trial Details May 2012

In attempting to determine how many patients had been treated with gene therapy for eye disorders, I quickly found that no one was keeping track – at least no one that I could find.

So, I decided to try and get this data. I have now found reliable data for more than two-thirds of the 16 clinical trials underway and present this information in my new table. My latest table (available via Update 16) contains all of the newest data.

Editors Note: See Update 16 for access to the latest versions of the three tables.

Gene Therapy in Ophthalmology Update 12: First Gene Therapy Approval on the Horizon Jul. 2012

As Andrew Pollack writes in today’s NYTimes, “After more than two decades of dashed expectations, the field of gene therapy appears close to reaching a milestone: a regulatory approval. The European Medicines Agency has recommended approval of a gene therapy to treat a rare genetic disease.”

The therapy recommended for approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency, a disease that affects only several hundred people in the European Union and a similar number in North America.

People with the disease have a genetic mutation that prevents them from producing an enzyme needed to break down certain fat-carrying particles that circulate in the bloodstream after meals. Without the enzyme, so much fat can accumulate that the blood looks white rather than red.

The reason I believe that this is important is because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking eleven clinical trials involving the use of stem cells to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval, when it comes, will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 13: New Clinical Site for Usher Syndrome Clinical Trials  Jul. 2012

The Foundation Fighting Blindness and Oxford BioMedica announced funding for a second clinical site to conduct a gene therapy trial for Ushers Syndrome. The site will be the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts in Paris, and will join the ongoing clinical trial being held at the Oregon Health & Science University's Casey Eye Institute.

Gene Therapy in Ophthalmology Update 14: Early Positive Results in Ongoing Gene Therapy Wet AMD and Stargardt’s Disease Studies Aug. 2012

Last week, Oxford BioMedica and its partner Sanofi announced positive results in their ongoing gene therapy clinical trials for wet AMD and Stargardt’s disease. In an interim review of their Phase I (RetinoStat) and Phase I/IIa (StarGen) trials, the Data Safetly Monitoring Board (DSMB), an independent panel of specialists in the fields of ophthalmology, virology and vectorology, gave the go ahead to proceed to a final patient cohort in the Phase I study in the case of the RetinoStat trial, and to a third patient cohort in the Phase I/IIa study of the StarGen trial.

Gene Therapy in Ophthalmology Update 15: First Gene Therapy Treatment Approved! Nov. 2012

As I first wrote back in July (Update 12: First Gene Therapy Approval on the Horizon), the first approval of a gene therapy application in medicine was expected soon. It has now been accomplished. On November 2nd, the European Medicines Agency gave final approval to a gene therapy approach to treat a rare genetic disease.

The therapy, given approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency (LPLD), a disease that affects only several hundred people in the European Union and a similar number in North America.

The reason I am noting this accomplishment in this space, where I normally write about treatments for ocular diseases is, because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking twenty one clinical trials involving the use of stem cells (or cell threapy) to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 16: Current Tables Now Online Jan. 2013/May 2014

Access to the three updated tables of information about the companies and institutions active in gene therapy, the ophthalmic applications being pursued, and the clinical trials underway and completed.

Gene Therapy in Ophthalmology Update 17: Hemera Biosciences Obtains Initial Funding Mar. 2013

Hemera biosciences has obtained initial funding, along with the issuance of a US Patent covering their technology 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.

Gene Therapy in Ophthalmology Update 18: A RetroSense Update  Mar. 2013

Since I first wrote about RetroSense in November 2010, I have learned that they are using a unique technology, called Optogenetic Therapy to treat retinitis pigmentosa and dry AMD. Optogenetics combines gene therapy and optical methods to provide vision where there is none.

The gene therapy allows the delivery of an “opsin” that converts second- or third-order non-light sensitive cells to become light sensitive to mimic the function of rods and cones.

Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies Jun. 2013

Researchers at UCal Berkeley have found a gene therapy vector that can deliver genes deep into the retina via intravitreous delivery, instead of using a needle to deliver the virus sub-retinally.

This eliminates the need for a vitrectomy, anesthesia and a hospital stay to treat patients, allowing for a simple short office visit and injection into the vitreous, similar to the way anti-VEGF drugs for age-related macular degeneration are currently delivered.

Gene Therapy in Ophthalmology Update 20: Oxford BioMedica Gene Therapy Clinical Trials Resume Oct. 2013

As I have recently noted, both Oxford BioMedica and Genzyme had stopped recruiting for their respective gene therapy clinical trials this summer. Oxford announced the reason for its stoppage, but no word from Genzyme (and no response to my attempts to find out).

Well, Oxford announced today that it had resumed its clinical trial after receiving clearances from both the FDA and the French regulatory agency, ANSM.

Gene Therapy in Ophthalmology Update 21: New Gene Therapy Company, Spark Therapeutics, Launches Oct. 2013

Children’s Hospital of Philadelphia has spun out a new gene therapy company, Spark Therapeutics, that has taken over CHOP’s gene therapy programs. The new company takes over the advanced clinical trial for treating Leber’s Congenital Amaurosis, as well as an earlier stage trial for treating hemophilia B.

The Phase III clinical trial for Leber’s, is expected to be completed in mid-2015, and could become the first FDA-approved gene therapy treatment in the U.S.


Recently, I encountered a unique referral source, goldenretrevor/pra-research. This piqued my curiosity and I went to the site and took a look. It turns out that the site is run by the owner of a Golden Retriever, named Trevor, along with two Labrador Retriever siblings. It seems that Trevor had been diagnosed with photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA). This was discovered when the dog was a puppy and the owner decided to look into this disease to see if there was anything that could be done to prevent him from going blind.

In doing extensive research, the owner, Katie McCormick, discovered that there was little research being done in the field of PRA in animals, but that PRA is genetically similar to retinitis pigmentosa (RP) in humans, as one study noted, "Identical mutation in a novel retinal gene causes progressive rod-cone degeneration (prcd) in dogs, and retinitis pigmentosa in man." And, there was lots of research being done on RP.

In her blog entry on PRA Research, Katie describes how she set up a “Google Alert” using the terms “progressive retinal atrophy” and “retinitis pigmentosa” – which is how she found my Journal article on The Use of Gene Therapy in Treating RP and Dry AMD.

A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech  Feb. 2012

I originally contacted this company in November 2010, when they were still in “stealth mode” and weren't able to share details about what they were doing. Recently, the company got back in touch to provide an update, having announced, in December 2011, a clinical trial of their gene therapy approach to treating the wet form of AMD.

Since their approach is unique, and possibly “game changing” for the treatment of the wet form of AMD, I asked if I could prepare a writeup about the company and its technology for publication in my online Journal, and the co-founder and CEO Tom Chalberg agreed to answer my questions, as best as he could. So, here in their own words is what Avalanche Biotech is all about.

An Update on Avalanche Biotechnologies: A Potential Longer-Lasting Wet AMD Treatment? May 2014

With the news of a collaboration between Avalanche and Regeneron, we decided to update our initial report on Avalanche to describe what the collaboration is all about, as well as a brief update of the clinical trial underway using Avalanche’s Ocular BioFactory. Could this approach to treating wet AMD lead to fewer injections – once every 18 months or several years – in controlling this sight-robbing disease?

Thursday, May 08, 2014

An Update on Avalanche Biotechnologies: A Potential Longer-Lasting Wet AMD Treatment?

There is breaking news this week about Avalanche Biotechnologies and I would like to share it, as well as a brief update on the clinical trial underway using their proprietary gene therapy approach to treating the wet form of AMD.

(Editors Note: For a comprehensive look at the company, its people, and technology, please take a look at my original writeup, placed online in late February 2012: A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech.)

Now for the breaking news. On May 5th, in a joint announcement, Avalanche and Regeneron Pharmaceuticals said that they were undertaking a broad collaboration “to discover, develop and commercialize novel gene therapy products for the treatment of ophthalmic diseases. The collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche and Regeneron, and developed using the Avalanche Ocular BioFactoryTM, an adeno-associated virus (AAV)-based, proprietary, next-generation platform for the discovery and development and delivery of gene therapy vectors for ophthalmology.”

Under the terms of the agreement, Avalanche will receive an upfront cash payment, contingent payments of up to $640 million upon achievement of certain development and regulatory milestones, plus a royalty on worldwide net sales of collaboration products. The collaboration covers up to eight distinct therapeutic targets, and Regeneron will have exclusive worldwide rights for each product it moves forward in clinical development. In addition, Avalanche has the option to share in development costs and profits for products directed toward two collaboration therapeutic targets selected by Avalanche.

As part of the agreement, Regeneron has a time-limited right of first negotiation for certain rights to AVA-101, Avalanche's gene therapy product targeting vascular endothelial growth factor (VEGF) currently under development for the treatment of wet age-related macular degeneration (AMD), upon completion of the ongoing Phase 2a trial.

"We look forward to the opportunity to collaborate with Avalanche, a leader in the field of next-generation gene therapy technologies," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "This collaboration highlights the commitment by Regeneron to invest in potentially breakthrough therapies that could benefit patients with sight-threatening diseases."

"We are excited to work with Regeneron to discover and develop novel gene therapy medicines for serious eye diseases," said Thomas W. Chalberg, Ph.D., co-founder and Chief Executive Officer of Avalanche Biotechnologies. "The collaboration will bring together Avalanche's novel platform technology with Regeneron's proprietary molecules and research capabilities, with the goal of creating a new class of next-generation biologics in ophthalmology. Regeneron is a terrific partner for their scientific leadership, as well as their product development capabilities and commercialization track-record."

For those of you not familiar with Regeneron Pharmaceuticals, they are a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron commercializes medicines for eye diseases, colorectal cancer, and a rare inflammatory condition, and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, oncology, rheumatoid arthritis, asthma, and atopic dermatitis.

In the eye disease field, their major product is Eylea, an anti-vascular endothelial growth factor (VEGF) agent that is intravitrealy injected for the treatment of  wet AMD, in competition with Roche/Genentech's Avastin, and Lucentis.

The problem with the use of the current anti-VEGF drugs is the need for up to eight to twelve injections yearly, to maintain the gains in visual acuity and/or prevent the re-occurrence of the underlying neovascular degeneration. The reason for the collaboration with Avalanche is that its BioFactoryTM is expected to deliver a therapeutic protein to combat wet AMD for at least 18 months and, potentially for several years, from a single injection. (For more about this technology, again, please see my initial writeup.)

And that leads to the recent clinical trial update provided by founder and CEO, Thomas Chalberg at the the Angeogenisis, Exudation and Degeneration 2014 Conference, held in Miami, FL on February 8, 2014:

Retina Today, April 2014

Subretinal delivery of an ocular gene therapy drug was well tolerated, required fewer injections of anti-VEGF, and improved visual acuity in a phase 1 randomized clinical trial, reported Thomas W. Chalberg, PhD, at Angiogenesis, Exudation, and Degeneration 2014.(1)

One hundred microliters of AVA-101 (Ocular BioFactoryTM, Avalanche Biotechnologies) was injected subretinally in patients. Anti-VEGF protein levels ramp-up over 6 to 8 weeks, during which 2 injections of ranibizumab (Lucentis) were given. After 8 weeks, ranibizumab was only given to the treatment group on a prn basis as rescue therapy.

Patients were tracked for 12 months after injection and came in for monthly visits. The control group, which did not receive an injection of AVA-101, required a mean 3 injections of ranibizumab during the 12-month period. The treatment group required a mean 0.3 ranibizumab injections over the same period.

Patients received ranibizumab injections if fluid appeared on OCT or fluorescein angiography, or if there was vision loss attributable to increased area of choroidal neovascularization.

Patients in the study had experience with anti-VEGF treatment, averaging 18 intravitreal anti-VEGF treatments prior to study enrollment.

“Because these patients are coming heavily pre-treated, we didn’t necessarily expect them to gain additional vision,” Dr. Chalberg said. “But treated patients actually gained between 9 and 12 letters over 12 months.”

Dr. Chalberg reported no drug-related adverse events, retinal tears, or retinal detachments. Procedure-related adverse events were minor and self-resolving.

“Ocular gene therapy might be a long-term viable option for patients with wet AMD,” Dr. Chalberg said.

AVA-101 is a strand of therapeutic DNA packaged inside an adeno-associated virus (AAV), which, when injected subretinally, up-regulates the body’s production of anti-VEGF. Subretinal injection appeared to be safe and was well tolerated, Dr. Chalberg reported, and allowed AVA-101 injections to better stimulate anti-VEGF production than if delivered intravitrealy.

Dr. Chalberg reported that an on-going phase 2A study currently has 40 patients enrolled.


1. Chalberg TW. Anti-VEGF gene therapy: early clinical results using the Ocular BioFactoryTM in wet AMD. Paper presented at: Angiogenesis, Exudation, and Degeneration 2014; February 8, 2014; Miami, FL.

Thursday, April 10, 2014

A New Approach for Repairing/Rejuvenating Damaged Photoreceptors and Other Retinal Tissue for Restoring Vision

Over the past several years, I have written about new technologies for treating retinal diseases, including the use of drugs (Avastin, Lucentis and Eylea for wet AMD), laser treatment (Ellex’s 2RT - Retinal Regeneration, for dry AMD), and the use of stem cells and gene therapy for a wide range of ophthalmic diseases.

Earlier this year, I became aware of a new company, jCyte, who was investigating the use of retinal progenitor cells to replace damaged or destroyed photoreceptors to restore vision to those whose photorecptors had stopped working, especially in those with the latter stages of  retinitis pigmentosa (RP). I was aware that Advanced Cell Technology was also in the early stages of doing research with retinal progenitor cells. I decided the best way of learning about this unique approach to restoring photoreceptor activity (and perhaps, vision) to those afflicted with RP and other retinal degenerative diseases, was to undertake some research and write about it.

In doing the background research, I discovered that two other companies, ReNeuron and California Stem Cell, are also involved in this area of technology. Here is what I have learned to date.


In order to learn about jCyte, I contacted Dr. Henry Klassen, it’s founder and Associate Professor of the Gavin Herbert Eye Institute and its Stem Cell Research Center at the University of California, Irvine (UCI), and learned about his new company and about how its program to restore vision to those with RP will evolve.

In doing additional background research, I quickly discovered that ReNeuron, a UK biotechnology company, was also working towards that same goal and, in fact, was working with Dr. Michael Young of Schepens Eye Research Instititute who, it turned out, was a past co-author with Dr. Klassen’s in working on pre-clinical animal studies in this field.

In this writeup, I intend to tell you what retinal progenitor cells are, what they can do, and why this might be an important technique for restoring vision in those with damaged or destroyed photoreceptors.

I will also tell you about the companies involved, where the state of development stands and provide a possible timetable to the future, including the pre-clinical work underway and the road to human clinical trials.

I have also included some information about competitive activities, and where these alternative techniques/technologies for restoring vision for those with damaged photoreceptors stand.

The Problem

There is a group of  retinal degenerative diseases that constitute a significant source of visual disability in both the developed and undeveloped world, and where current therapeutic options are quite limited.

For instance, the loss of photoreceptor cells, as seen in the later stages of retinitis pigmentosa (RP), geographic atrophy (GA) in dry AMD, and the late stages of Stargardt’s disease (SMD), results in permanent visual loss for which no restorative treatment is as yet available. But, the notion that photoreceptor cells might be replaceable in therapeutic settings has been given recent support by experimental work in animal models [1].

The Technology

What are progenitor cells and what can they do?

A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and, can be pushed to differentiate into its "target" cell. The most important difference between stem cells and progenitor cells is that stem cells can replicate indefinitely whereas progenitor cells can divide only a limited number of times.

Most progenitors are described as multipotent, not pluripotent. In this point of view, they may be compared to adult stem cells, but progenitors are said to be in a further stage of cell differentiation. They are in the "center" between stem cells and fully differentiated cells. The kind of potency they have depends on the type of their "parent" stem cell and also on their niche, in this case, eye-derived progenitor cells that have partially differentiated into retinal cells.

Retinal progenitor cells (RPCs)

Retinal progenitor cells are self-renewing cells capable of differentiating into the different retinal cell types including photoreceptors (rod and cone cells), even neuron cells, and they have shown promise as a source of replacement cells in experimental models of retinal degeneration.

The Companies Involved

Advanced Cell Technology (ACT)

ACT’s primary research program uses retinal pigment epithelium (RPE) cells derived from embryonic stem cells in the treatment of dry AMD, Stargardt’s disease, and soon myopic macular degeneration (MMD). The company is currently injecting these hESC-derived RPE cells subretinally into humans in three clinical trials, in which more than 30 patients have been treated to date, with no reported problems of safety and, in most cases, with reported improved vision. In one case, a dry AMD patient reportedly went from 20/400 vision, to 20/40 vision within several weeks of treatment. [2]. We believe that in this case, his dormant (but still alive) photoreceptors were re-activated by the RPE cell treatment.

The MMD clinical trial has received IND approved and is expected to begin shortly.

The company is also undertaking early pre-clinical animal studies in their laboratories with several types of  progenitor cells.

As reported by Dr. Robert Lanza, the company’s CSO at the last shareholder’s meeting in October 2013 [3]:

 “We have, as I mentioned earlier, a number of other cell types that we are studying in the eye field, including our retinal neural progenitors, photoreceptor progenitors, and also ganglion progenitors. As regard to the retinal neural progenitors, we have looked at these cells in animals that have retinal degeneration...and we can see very significant rescue of their activity.”

“We also have a program that we are pursuing using these photoreceptor progenitors. When you inject these into animals subretinally, what we were able to actually see here in the first week...the cells incorporating into the retina and within only three weeks you can see them moving into the outer nucleated layer and integrating.”

“We are also studying the photoreceptor progenitors. We are also looking to see if we can recover visual function and retinal structure using those. We also want to test those both in vitro and in vivo in terms of using conditioned media in the secreted factors. We are also studying our ganglial progenitors and we are continuing to look at those in animals for prolonged term survival of the transplanted cells, as well as for the protection or replacement of the host ganglial cells. We are also looking at using these cells in the optic nerve regeneration model.”

Systemically delivered Photoreceptor Progenitor cells reversed the progression of photoreceptor degeneration – and promoted regeneration of both Rods and Cones.[4]

More recently, the company updated the status of its progenitor programs in its recent Form 10-K for 2013[5]:

Photoreceptor Progenitor Program

We have developed a human photoreceptor progenitor cell. We believe that our photoreceptor progenitor cells, [derived from embryonic stem cells (hESCs)], are unique with respect to both the markers they express as well as their plasticity, meaning that they can differentiate into both rods and cones, and therefore provide a viable source of new photoreceptors for retinal repair. In addition, the photoreceptor progenitors appear to secrete neuroprotective factors, and have the ability to phagocytose (digest) such materials as the drusen deposits that build up in the eyes of dry AMD patients, and so may provide additional benefits beyond forming new photoreceptors when injected into the subretinal space in the eyes of patients. We will continue our preclinical investigation in animal models, establish appropriate correlation between integration of the transplanted cells and visual function in the animals, and then consider preparation of an IND and/or IMPD application to commence clinical studies with these cells.

Retinal Ganglion Cell Progenitor Program

In the United States alone, approximately 100,000 people are legally blind from glaucoma. The only proven treatment is drug therapy or surgically lowering the intraocular pressure, but many patients lose vision despite receiving these treatments. In glaucoma, retinal ganglion cells degenerate before photoreceptors are lost. We are currently conducting pre-clinical research and development activities regarding differentiation of stem cells into retinal ganglion cells and demonstration of the ability of those cells to protect against elevated intraocular pressure in glaucoma models. We have succeeded in generating a unique human ganglion progenitor cell which, when injected in animal models of glaucoma, appear to protect against damage and to form new ganglion nerve cells. We will continue our preclinical investigation in animal models, establish appropriate correlation between integration and visual function in the animals, and then consider preparation of an IND and/or IMPD application to commence clinical studies with these cells.

Neuroprotective Biologics

In the course of our work with various progenitor cells for treating ocular degenerative diseases, we have discovered that certain progenitor cells not only have the ability to participate directly in the formation of new tissue in the eye, but also were able to exert a neuroprotective effect that reduces the rate of degeneration of native photoreceptors in the animals' eyes, for example, in animal models of macular degeneration. These cells appeared to also be a source of neuroprotective paracrine factors; biological agents which may themselves be useful as drugs. Further, we observed that these protective effects were uniquely produced by particular progenitor cell sub-types. The restriction of this protective activity to only a certain progenitor cell type permits us to examine which factors are differentially produced by these cells as compared with other closely related progenitor cells which do not seem to secrete any protective agents. We anticipate that the neuroprotective agent(s) that we may ultimately develop as drug candidates may be useful not only in retinal diseases and dystrophies, but may have broader applications in central nervous system and peripheral nervous system diseases and disorders, including diseases causing cognitive function impairment, movement disorders such as Parkinson's Disease, and ischemic events such as caused by stroke.

This progenitor cell work is in the pre-clinical stages and not yet ready for human clinical testing.

Californis Stem Cell, Inc. (CSC)

In early February, California Stem Cell, Inc. (CSC) announced the initiation of a collaborative study with the University of California, Irvine (UCI), to create a transplantable 3D retinal tissue.[6] The study, funded by a $4.5 million grant from the California Institute of Regenerative Medicine (CIRM), is a continuation of methods pioneered by CSC scientists and researchers at UCI in 2010 [7], and will investigate the potential of improving a patient's visual function by transplanting human stem cell-derived three-dimensional (3D) retinal tissue into their retina.

California Stem Cell, using its specialized cGMP manufacturing facility and regulatory personnel, will differentiate human stem cells into retinal progenitor cells. These cells will then be co-cultured with stem cell-derived retinal pigment epithelium to create a 3D tissue structure suitable for transplantation. Proof of concept in-vivo studies will take place at UCI's Sue & Bill Gross Stem Cell Research Center, under the auspices of Dr. Magdalene J. Seiler. Transplants are expected to develop into mature retina, interact with the host tissue, and subsequently improve the vision of retinal degenerative recipients. The study, if successful, could lead to new treatments for incurable retinal diseases such as retinitis pigmentosa and age-related macular degeneration, leading causes of vision loss for people age 50 and older.

CSC President & CEO Hans Keirstead, Ph.D. (formally with UCI) will lead the study's work at CSC. "This study establishes a valuable partnership between ourselves and a team of very talented scientists at a university known for its excellence in research," said Keirstead. "California Stem Cell looks forward to making a meaningful contribution to work that has the potential to help millions suffering from life-altering retinal diseases."

This work is in the very early pre-clinical animal testing stages.

Editors Note: In late breaking news, it was announced on April 14th that CSC has been acquired by NeoStem, Inc. The deal is expected to close in May.


jCyte has developed methods, that utilize human, fetal-derived, retinal progenitor cells (hRPCs), that have been partially developed into retinal cells, to activate degenerating host photoreceptors and replace and/or reactivate, in this case the cones, lost to disease, in those with retinitis pigmentosa (RP).

JCyte’s work will initially target cone cells because they provide central vision and the ability to read, drive and recognize faces. (Although, rod cells should also be affected.) The work will include growing pharmaceutical-grade progenitors, testing them for safety and efficacy in animal models, and then launching a clinical study for severely impaired RP patients, to prove safety and efficacy in humans.

jCyte's research is currently supported by several resources including The Discovery Eye Foundation and two awards from CIRM (the California Institute for Regenerative Medicine), including a $4 million CIRM's Early Translation II Award [8] and more recently a $17 million Therapy Development grant [9]. Dr. Klassen's project was also accepted into the Therapeutics for Rare and Neglected Diseases (TRND) program established by the National Institutes of Health to speed the development of new treatments for rare and neglected diseases. TRND will provide him with specialized expertise and resources to help advance his efforts [10].

Dr. Klassen intends to seek further funding to translate this cutting-edge discovery into clinical drug and cell therapy, via submission to the FDA to launch a clinical trial.

In an update posted on his website in November 2013 [11], Dr. Klassen reported that, “The team remains hard at work in the effort to bring retinal progenitor cells to clinical trials. The work being conducted now is centered on accumulating the evidence we need to provide to the FDA in order to get approval. Prior work has set the stage by showing what is possible using these cells, but now everything has to be repeated on a larger scale, with extensive documentation, and using the same cells that will be used in patients. This is known as the Pre-Clinical Phase of the project and, as such, it is the stage just before trials begin. The major objective of the Pre-Clinical Phase is to demonstrate safety and efficacy of the product in animal models as a basis for initiating studies in humans. It is a lot of work and would take a long time if everything was done sequentially so, with the help of CIRM, we are approaching the various projects in parallel to accelerate progress. Still, it can be expected to take about a year to complete. As the results of theses studies come in, they will be collected to form the body of what is known as an Investigational New Drug (IND) application, which is the formal document that goes to the FDA.”

If things go as planned, jCyte should complete its pre-clinical work and be prepared to submit its NDA by late 2014, for a human clinical trial for patients with severe RP. The patients will be injected with hRPCs in their worst-seeing eye to determine safety and efficacy, hopefully, beginning sometime in early 2015.

Other targeted conditions, once safety and efficacy are shown in the RP trial, could include geographic atrophy (GA) found in dry AMD, and replacing destroyed photoreceptors in those suffering from Stargardt’s Disease (Stargardt’s Macular Dystrophy [SMD]).


One of the more ambitious stem-cell treatments nearing human study is being developed by ReNeuron, a company from the United Kingdom. Its retinal progenitor treatment replaces photoreceptors lost to retinitis pigmentosa. When transplanted in the retina, ReNeuron researchers believe that the partially developed cells will mature into fully functional photoreceptors. The company hopes to launch a clinical trial this year. Previously funded by the Foundation Fighting Blindness, Michael Young, Ph.D., of Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, conducted much of the research making this treatment approach possible. His work included the development of a biodegradable scaffold for growing and organizing the cells prior to transplantation. The structure increases the chances of survival and integration of the therapeutic cells.[12]

In September 2013 [13], ReNeuron was granted an orphan designation by the U.S. Food and Drug Administration (FDA) and the European Commission for its emerging retinitis pigmentosa (RP) treatment, known as ReN003 (hRPCs derived from fetal tissue). Given to potential treatments for rare conditions that are life-threatening or chronically debilitating, "orphan" status provides a company with development incentives, tax credits and market protections for therapy development.

The designation bolsters ReNeuron's plan to launch a Phase I/II clinical trial for ReN003 in mid-2014. The company is partnering with the Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, to develop the treatment. According to Dr. Young, a lead investigator on the project at Schepens, ReNeuron plans to initiate the study at the Mass Eye & Ear Infirmary in the United States, and later extend it to sites in Europe.

Other Research Programs:

There are also several university-based projects underway, including that of Prof. Robin Ali at University College London [14], and in the lab of Thomas Reh at the University of Washington in Seattle [15].

Competing Technologies for Restoring Vision to Those with Damaged/Destroyed Photoreceptors

In addition to the programs using retinal progenitor cells, there are several efforts underway to provide vision to those who have lost it because of damaged or destroyed photoreceptors.

I will list just a few of these:

The Use of Stem Cells – Several companies/institutions are in clinical trials [16] using stem cells to treat those with Stargardt’s disease, dry AMD, and retinitis pigmentosa.

The Use of Gene Therapy – Gene therapy is also actively being used [17] in the treatment of dry (and wet) AMD, Stargardt’s disease, and retinitis pigmentosa.

Optogenetics – An offshoot of gene therapy, wherein a photoactive dye is delivered via a virus carrier into neural tissue (ganglion cells, bypassing damaged photoreceptors) and is activated by light signals sent into these activated tissues, which in turn sends electrical signals along the optic nerve to the brain [18]. Several companies and institutions are currently doing animal work in preparation for undertaking human trials, including Eos Neuroscience, Gensight Biologics, RetroSense Therapeutics, and the Institute de la Vision in Paris [19], along with work being done at Cornell Univ. by Dr. Sheila Nirenberg [20].

Retinal Implants – Several companies have developed and are currently marketing devices that sit on the surface of the retina and use cameras, or other optical means to send a signal to the electrodes implanted on the retinal surface that in turn sends a signal to the brain simulating visual inputs [21].

Retinal Regeneration – a laser treatment whereby a mild laser dose is imposed onto the RPE layer as a means of “stimulating” the RPE cells to release enzymes that are capable of “cleaning” Bruchs membrane, thereby rejuvenating the retina and restoring vision [22].


I personally believe that the use of retinal progenitor cells to rejuvenate or repair damaged photoreceptor cells in those people with degenerative retinal diseases, is an important step in the right direction. If, in the clinical trials scheduled to begin in late-2014 or 2015, this technique does restore vision in people that have lost it due to damaged or destroyed photoreceptors, it will become one of the great advances in the battle of fighting blindness.


5. ACT Form 10-K, April 1, 2014

7. Three-dimensional early retinal progenitor 3D tissue constructs derived from human embryonic stem cells, Gabriel Nistor et al, Journal of Neuroscience Methods, April 2010.

Henry J. Klassen, M.D., Ph.D.,, Therapeutics for Rare and Neglected Diseases(TRND) program at the NIH's National Center for Advancing Translational Sciences (NCATS), October 2, 2013

11. November 2013 Update from Dr. Henry Klassen, jCyte News, November, 2013

12. Several New Stem Cell Clinical Trials Poised to Begin in Two to Three Years, Dr. Stephen Rose, Eye on the Cure (FFB), July 12, 2013

14. New Breakthrough: transplantation of photoreceptors from retina grown `in a dish', Prateek Buch, UCL EyeTherapy blog, July 22, 2013

15. Efficient generation of retinal progenitor cells from human embryonic stem cells, Lamba et al, University of Washington, Seattle, WA,  PNAS, July 2006

19. Gene Therapy Companies/Institutions Active in Ophthalmology, Irv Arons’ Journal, January 2014

21. Ibid, section on Retinal Prostheses

22. Ellex 2RT Updated Clinical Results: ARVO 2011, Irv Arons’ Journal, May 2011