Retinal degeneration represents a group of blinding diseases that are increasingly impacting the health and well being of Californians. It is estimated that by 2020, over 450,000 Californians will suffer from vision loss or blindness due to the age-related macular degeneration (AMD), the most common cause of retinal degeneration diseases in the elderly. AMD is a progressive ocular disease of the part of the retina, called the macula, which enables people to read, visualize faces, and drive. The disease initially causes distortion in central vision, and eventually leads to legal blindness.
A layer of cells at the back of the eye called the retinal pigment epithelium (RPE), provide support, protection, and nutrition to the light sensitive cells of the retina; the photoreceptors which consist of rods and cones . The dysfunction and/or loss of these RPE cells play a critical role in the loss of the PR’s and hence the blindness in AMD. Effective treatment could be achieved by proper replacement of damaged RPE and retinal cells with healthy ones. More specifically, the regenerated and restored RPE layer would prevent the irreversible loss of the PR’s. However, the lack of a feasible approach to restore the RPE cells has prevented the realization of a potential therapy.
Recent advances in knowledge and technology of human embryonic stem (hES) cells brings new hope for the development of cell replacement treatment. hES cells are capable of unlimited self-replication and production of different cell types. RPE cells derived from hES cells are a potentially unlimited and robust source for regenerating RPE.
We hypothesize that the dysfunction and/or loss of RPE can be overcome by regenerating and restoring the RPE through the transplantation of functionally polarized RPE monolayers derived from hES cells. Such RPE cells derived from hES can then be transplanted into the eye, using minimally invasive surgical procedures saving the PR from dying.
Our group is composed of unique multidisciplinary members who collectively have more than two decades of experience in efforts to restore sight to the blind as well as retinal cell transplantation and stem cell research. Our plan for this grant is to use our expertise and infrastructure to show to the FDA the success of our preclinical tests using hES derived RPE cells in order to get approval to conduct a clinical trial in patients at risk of vision loss due to AMD.
Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among the elderly. Based on the fact that California is one of the most populated state in the Unites States (38 million population in 2007), and a greater percentage of its population will be 65 years or older. It is estimated that over 450,000 of Californians will suffer from AMD with severe vision impairment by 2020. Even using National Eye Institute numbers from 2003 and adjusting it for the population of California, the costs for California exceed $8 billion (http://www.nei.nih.gov/eyedata/hu_estimates.asp). Since the introduction of the anti-VEGF drug Lucentis by Genentech in 2006, the cost for the treatment for AMD has even further sky rocketed. For example, the cost of these monthly injections to treat all of the new cases of neovascular (wet) AMD in 2008 in California alone would exceed 9 billion (single patient costs per year often is approximately $25k/year). Moreover, studies have shown that the devastating consequences of AMD include the progressive loss of independence and productivity, and increased risks of falls, fractures, and depression among diseased population. So this is not only a problem of the individual quality of life, but also an issue of increasing public health burden and concern.
In this study, we will test the feasibility of treating AMD through the transplantation of human embryonic stem cells that have been treated to differentiate into retinal pigment epithelial cells (RPE); one of the key cell types known to primarily degenerate or die in AMD. The approach of regenerating the RPE cell layer has many advantages over regenerating photoreceptors and is much more likely to be achieved in the near future. The biggest advantage to RPE cell layer regeneration is that it is preventative and protects or rescues the photoreceptors from degenerating. Also, since it is not a neuronal cell line it does not need to form synapses with the host; a much more difficult task. The success of our preclinical experimentation with RPE replacement therapy will be seamlessly and quickly transferred into clinical trials to develop novel treatments for AMD. Ultimately, hundreds of thousands of Californians with AMD would benefit from our research, with improvement in quality of life and reduced morbidity. The California economy will significantly benefit from this work through potential reduced costs for health care and social welfare. We also envision that our research would lead to a new industry and hence many more employment opportunities and also add to the revenue generated by the state of California. Also our efforts at the University level in California would lead to new curricula in stem cells and regenerative medicine and thus educate the work force of the future.
The goal of this proposal is to develop a cell-based regenerative therapy for dry Age related Macular Degeneration (AMD) using retinal pigment epithelium (RPE) derived from human embryonic stem cells (hESC). Dry AMD is associated with deterioration of the retina and is a leading cause of irreversible vision loss and blindness in the elderly. The retinal pigment epithelium (RPE) is a layer of cells that underlies the light sensitive retinal photoreceptors (PR) and provides support, protection and nutrition to the PR. Dysfunction or loss of RPE cells is thought to be a major factor in the pathology of AMD, leading to subsequent loss of PR and eventual blindness. The applicant hypothesizes that the loss of RPE can be overcome by transplantation of a functional RPE monolayer into the subretinal space, and that this will in turn prevent the irreversible loss of the PR. The applicant proposes to optimize procedures to derive a functional RPE monolayer from hESC, comparing two different hESC lines grown on different synthetic biomatrix substrates. Various biocompatible matrices will be developed and evaluated, with the aim of identifying an ideal substrate for hESC-RPE delivery, function and survival. The RPE monolayer will be surgically implanted into preclinical models in two species for safety and efficacy testing. PR health will be analyzed using standard histology as well as noninvasive imaging methodology. Long-term animal studies will be conducted to exclude tumor formation. As prerequisites for filing an Investigational New Drug (IND) application, methods will be developed for Good Manufacturing Practice (GMP) manufacture and product release, and Good Laboratory Practice (GLP) safety testing studies will be conducted.
This proposal was recommended for funding based on the strong scientific rationale, supported by both preclinical and clinical data, excellent team, clear unmet medical need, and feasibility. In addition, this was considered a good case to test the concept of hESC-based therapy because the eye is normally a contained and potentially immunoprivileged site.
Reviewers agreed that a significant body of both research and clinical data support the applicant’s rationale for RPE replacement. RPE have been generated from ESC in two different species and more recently from hESC. In addition, autologous RPE transplantation represents one approach to the treatment of AMD and has been shown to work in humans. Thus proof-of-principle of the efficacy of RPE transplantation already exists. The proposed approach offers some potential advantages over other available approaches for treating dry AMD. One potential advantage is that compared to autologous cells, which would most likely be from an elderly patient, hESC-derived cells are expected to be more proliferative and more robust, and hence better able to sustain themselves in a disease environment. A second advantage comes from the approach of delivering the RPE in the form of a monolayer, thought to be superior to a cell suspension because the underlying Bruch’s membrane in AMD is abnormal and cannot provide an optimal substrate for the attachment and further differentiation of injected cell suspensions. Additionally, reviewers felt that relative to other sites, the eye is normally a contained site, making cell extravasation less likely and the retina is somewhat immune privileged, potentially lessening the risk of immune rejection. It is unclear whether the containment and immune privilege is maintained in the diseased state and the applicants propose a local steroid treatment should immunosuppression be required. In addition, having an already-developed, non-invasive method of imaging the retina that will allow follow-up analysis was viewed as a plus. Reviewers were in agreement that the science of this project is mature and the replacement therapy appealing.
Reviewers concurred that this proposal addresses a problem of major significance. Dry AMD affects a large number of Americans and can result in significant vision loss. As the population ages, AMD will become an even more important cause of morbidity and cost for society. Reviewers were in agreement that this study is timely, since there is currently no reliable, or FDA-approved, treatment for dry AMD. Successful translation of this proposal into a clinical therapy would likely have a significant impact on the treatment of a common and severely debilitating disorder.
Feasibility of many of the key steps in the proposal has already been demonstrated. The hypothesis that restoration of proper RPE-PR interactions can prevent PR degeneration is supported by both experimental and clinical data. For example, published literature on autologous RPE transplantation, used in the treatment of AMD, has shown that visual function can be restored and maintained in humans. RPE differentiation and purification protocols have already been worked out and the investigators present compelling data that they can routinely generate high yields of hESC-derived cells with many of the phenotypic characteristics of mature RPE cells. According to one reviewer, this presents a firm foundation for this study. The investigators present proof-of-concept data in preclinical models of retinal dystrophy indicating that hESC-derived RPE can engraft and rescue PR based on histology, although they have not yet shown functional benefits. This was judged as a weakness by some of the reviewers. However, the proposal does describe planned studies in 2 preclinical models to assess functional improvement and these will be critical milestones. One minor criticism was that the planned studies will not be using an established AMD model and hence will not specifically address efficacy in the context of AMD. One reviewer commented that such a cellular therapy is a very attractive option given the small number of cells likely to be required (because of this, manufacture of clinical quantities is very doable). One reviewer raised a minor caveat that because this is an invasive procedure involving the retina, it may restrict the approach, at least initially, to late stage disease where it may be difficult to show benefit. The reviewer commented that in general, it is easier to preserve vision than to restore it. However, this reviewer agreed that developing a strategy to regenerate defective RPE is certainly an excellent approach in the treatment of this disease. While the risk of teratomas was generally thought to be minimal (in part because the eye is a contained site), reviewers raised some concern that immune rejection might become a bigger problem than anticipated.
The preclinical plan is focused, and adequately addresses all necessary activities for IND filing. Reviewers concurred that the project milestones provide quantifiable endpoints and reliable indicators of the project’s successful progress. Collectively, these milestones represent a focused plan of research leading to the IND. The timeline is feasible. The development work to be done with the synthetic biomatrices is the least complete and represents the highest risk to the timeline for IND filing. Because the regulatory path is more complex for combination therapies (cells plus biomatrix), reviewers recommended that the team conduct an early (pre-pre-IND) meeting with the FDA.
Reviewers concurred that the team is strong, well thought out, well integrated, and likely to successfully achieve an IND. The PI has been a pioneer in retinal transplant surgery and was considered by all to have the experience necessary to manage a translational research project of this scope. The Co-PI has a well-established track record and was responsible for the recent derivation of RPE from hESC. The Partner-PI has made a number of seminal contributions to the development of cell-based therapies for AMD and has unquestionable experience in RPE transplantation models. With the Collaborative Funding Partner, the team has amassed a wealth of expertise from internationally recognized scientists in the appropriate fields, and brings together complementary expertise from stem cell biology, retinal surgery, differentiation of RPE from hESC and imaging, as well as all the necessary expertise for meeting GLP and GMP criteria. Collectively, the multidisciplinary team represents an appropriate mix of basic research, clinical, and management skills to ensure successful completion of the project. Reviewers had mixed opinions on whether there is sufficient biomatrix expertise on the team. The leadership plan is well formulated and should ensure coordinated activities across the team. The total budget requested for this project appears appropriate.
In summary, there was consensus that this proposal has a strong scientific rationale, that it addresses a serious unmet medical need, and that the science is at a point that makes it feasible to move to IND filing. In addition, the accessibility and relative ease of imaging retinal tissue combined with the need for only minimally invasive surgical procedures make this an attractive approach. The team is excellent and likely to meet the objective of a successful IND filing.
A motion was made to move the application from Tier 2 to Tier 1, Recommended for Funding. Reviewers argued that this is an excellent case with which to pioneer stem cell approaches and move stem cell therapy forward into the clinic. This conclusion was based on the suitability of the eye as a target tissue for testing early stem cell therapies. The panel noted the unique proposed use of a synthetic substrate which was seen as a good approach for stem cell therapy that could advance the field. The motion carried.