Disease Team Planning
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 retinal photoreceptors (PR’s), light sensitive 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 human hES 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 can then be transplanted into the eye, using customized surgical procedures and instruments 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 stage of this grant is to use our expertise and infrastructure to study and ultimately show the success of using hES derived RPE cells to the FDA in order to get approval to conduct a clinical trial in patients blind due to AMD.
Statement of Benefit to California:
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 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 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 starting 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 lead to 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.
Executive Summary The applicant proposes the development of a Disease Team that will address age-related macular degeneration (AMD), a serious and common cause of visual impairment throughout the world. AMD results either from abnormal blood vessel growth or atrophy of the retinal pigment epithelium underlying the macula. Currently, AMD resulting from abnormal blood vessel growth (the ‘wet’ form) can be treated with agents that inhibit vascular endothelial growth factor (VEGF) but there is no treatment for the so called ‘dry’ forms that result from retinal pigment epithelium atrophy. This project proposes to use transplantation of human ES cell-derived retinal pigment epithelial cells to maintain the integrity of the macula. Reviewers felt that the scientific concept and preliminary data underlying this proposal were very good. The eye was viewed as a great target due to being contained, well-studied, and more immune-privileged than some other tissues. One reviewer offered that the science of this project is mature and the replacement therapy appealing. The program director is extremely well-qualified and has put together a good team that includes important complementary expertise in human embryonic stem (ES) cell biology and retinal pigment epithelium cell biology. These were highlighted as strengths of the proposal. Animal data in support of this concept is still incomplete as no efficacy has yet been demonstrated and this shed some doubt on the project’s ability to make it to the clinic in 5 years. However, reviewers felt the current animal data is promising and, once in place, the experience of the applicants would make clinical application very fast. The planning approach was found to be well thought out and considered the relevant issues for translation such as access to GMP facilities, interactions with FDA, and clinical trial design. Overall, the panel felt that the planning should allow a comprehensive final proposal to be developed. Reviewer Synopsis This project targets age-related macular degeneration, a serious and common cause of visual impairment throughout the world and results either from abnormal blood vessel growth or atrophy of the retinal pigment epithelium underlying the macula. AMD resulting from abnormal blood vessel growth (the ‘wet’ form) can be treated with agents that inhibit VEGF but there is no treatment for the so called ‘dry’ forms that result from retinal pigment epithelium atrophy. This project proposes to use transplantation of human ES cell-derived retinal pigment epithelial cells to maintain the integrity of the macula. Reviewer One Comments Concept: The evidence that the retinal pigment epithelium supports the overlying retina is good and transplantation of retinal pigment epithelium has been shown to have clinical benefit. However, it is important to note that these transplants were performed in cases where there was a clearly defined defect in the retinal pigment epithelium rather than a widespread degeneration. The hypothesis here is that transplantation of retinal pigment epithelial cells that can be derived from ES cells will be therapeutic. In support of this, sub-retinal injections of these cells will provide some rescue in a rat model of AMD. The authors argue that this rescue might reflect a transient trophic effect rather than reconstitution of the normal anatomical arrangement between photoreceptor and retinal pigment epithelium, and that transplantation of highly differentiated cells is likely to be even more effective. The eye represents an optimal target for stem cell therapies based on accessibility and the presence of a second (unmanipulated) eye, should adverse outcomes follow treatment. Moreover, visual diseases are extremely disabling in a patient who may otherwise be completely well. The evidence that the retinal pigment epithelium supports photoreceptors is strong, and the transplantation studies are encouraging. However, it is clear that further work is required in these animal models and the field has not advanced to the stage of that in Parkinson’s disease or the lysosomal storage diseases where clear and unambiguous benefit in animal models is available. The ability to differentiate human ES cells into retinal pigment epithelial cells is clearly critical for this application. The method used by the applicant’s laboratory remains unpublished, but others have derived less pure populations used in the animal rescue experiments described above. Can it go to clinic in 5 years? There must be an element of doubt here, given the incomplete animal model data. However, the signs are that these animal experiments will show benefit and, once this is in place, the accessibility of the eye and the experience of the applicants would make clinical application very fast. Importance of problem and ability to advance stem cell medicine to the clinic: AMD is an enormous clinical problem and represents an excellent target for stem cell medicine. As proof of principle for the benefits that stem cell medicine might bring to degenerative diseases, this degenerative and common disease of the eye represents a highly attractive target. Principal Investigator: Track record of Principal Investigator The applicant appears extremely well qualified for this work. The PI is a retinal surgeon who has clearly made significant scientific and translational contributions as evidenced by publications, patents and awards for innovation. He has previously contributed to clinical trials of retinal transplantation and five spin-out companies in 5 years, which represents a significant achievement. Planning Approach: The applicant has clearly thought through the issues surrounding translation, GMP facilities, interactions with the FDA and clinical trial design; the consideration of this last point is particularly welcome. However, there is no obvious consideration about the necessary further animal studies and what would be considered sufficient proof to move forward to the next stage. The applicant has two partners who have important complementary expertise in human ES cell biology and retinal pigment epithelium cell biology. This is a real strength of the application. Other team members have been identified and the need to recruit more widely is appreciated. I think the combination of clinical need, accessibility of target and skills of the team will enable a competitive application to be delivered. Reviewer Two Comments Concept: Age related Macular Degeneration (AMD) is a major cause of blindness. Dysfunction or loss of retinal pigment epithelial (RPE) cells leads to loss of photoreceptor cells in both forms of AMD. Thus they propose therapy of using hES cells to re-establish a functional retinal pigment epithelial layer before the loss of photoreceptors. Photoreceptor translocation within the retina and autologous RPE transplantation have both been shown to work in humans. RPE have been generated from both mouse and primate ES cells and more recently hES cells. There is a non invasive method of imaging the RPEs which will allow follow-up analysis. Therefore the science of this project is mature and the replacement therapy appealing. The hypothesis is that monolayers of RPE will be even more beneficial due to being more highly differentiated and producing its own basement membrane. Principal Investigator: Dr. Humayun, Professor of Ophthalmology, Biomedical Engineering and Cell and Neurobiology at USC, also has a PhD in Biomedical Engineering and is a fellow of the American Institute for Medical and Biological Engineering. He has been a pioneer in retinal transplant surgery. He has won a number of awards and has NSF and DOE funding for bioelectronics laboratories as the PI. As director/ PI of these consortia of universities and industrial partners he has had experience in orchestrating large multi-investigator projects Planning Approach: The planning approach is well thought out and covers issues from cell lines to use to developing access to GMP facilities to interactions with FDA and clinical trial design. There already is a basic team with several other partners with specific expertise to be decided upon. Overall, the planning should allow a comprehensive final proposal to be developed.