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


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