Vision Loss

Coding Dimension ID: 
325
Coding Dimension path name: 
Vision Loss

Autologous Retinal Pigmented Epithelial Cells Derived from Induced Pluripotent Stem Cells for the Treatment of Atrophic Age Related Macular Degeneration

Funding Type: 
Early Translational I
Grant Number: 
TR1-01219
ICOC Funds Committed: 
$5 945 738
Disease Focus: 
Aging
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
The leading cause of visual loss in Americans over the age of 65 is age related macular degeneration (AMD) which occurs in both a "wet" and a "dry" form. Both forms of the disease are associated with loss of cells called retinal pigmented epithelium (RPE) which can lead to profound loss of central vision. Currently, there is no treatment that will reverse or prevent the loss of these cells and associated blindness. Nutritional supplementation with antioxidants, macular pigments and long chain PUFAs was shown to slightly reduce disease progression but the clinical reality is that 6-8% of people over the age of 75 are legally blind from this disease. Others have observed that RPE cells can be obtained from human embryonic stem cells and that these cells may be transplanted into eyes of animals with diseases that resemble human macular degeneration with RPE dysfunction. Potential problems with this approach to treating humans with this disease include the possibility that the embryonic stem cells from which the RPE are derived may be carried over into the eye and form tumors or elicit an immune response in the recipient eye since the cells are not from the same individual receiving the transplant. Recent advances in stem cell biology now make it possible to induce the formation of pluripotent stem cells (iPSC) from adult, or somatic, tissues of individuals; these cells, in turn, may be stimulated to form RPE cells. Thus, it would be possible to produce RPE cells from the skin or hair of the same individual who would receive the transplant. In order to do this, current technology requires the use of lentiviral vectors that integrate into the genetic material of the recipient cells. In addition, the efficiency with which the iPSC are formed is not very high and to produce these cells, and the derived RPE cells, it is necessary to use "feeder" cell layers and molecules derived from animals. In this research proposal, we will take advantage of novel chemistries and molecular biological techniques to develop iPSC from somatic tissues of patients with AMD and produce RPE cells that could then be used to replace damaged tissue in these patients' eyes. Using small molecules obtained from unique chemical libraries, we will enhance the efficiency of iPSC and RPE production from somatic cells and eliminate the use of animal cell "feeder" layers and supplements. Furthermore, we will use a unique procedure ("an episomal vector") to produce iPSC from somatic cells that does not require the use of potentially dangerous viruses and permanently integrated genetic material. If we are successful, a patient with early signs of AMD could come into their ophthalmologist's office, have a skin biopsy performed that could be used to obtain RPE cells that could then be transplanted into that individual's eye at a later date when their own RPE begin to degenerate, but before they have visual loss.
Statement of Benefit to California: 
As the population ages, individuals are prone to develop diseases of aging that significantly impact the quality of life in the "golden years." Foremost among these diseases is age related macular degeneration (AMD), a disease that affects the tissue in the back of the eye (the retina) used for vision. The central portion of this tissue, called the macula, is most affected in AMD and can lead to loss of fine, or "reading", vision. Vision loss occurs from two principal forms of the disease; the "wet" type involving the abnormal growth of new blood vessels and the "dry" type, involving degeneration and scarring of the macula. In both forms, special types of cells under the retina, called retinal pigmented epithelial (RPE) cells degenerate and contribute to the loss of vision. It is estimated that 15-20 million Americans over the age of 65 have AMD and 10-15% of these have vision loss secondary to the disease. Geographic atrophy (the dry type) affects 0.81% of the US population, equivalent to a prevalence of approximately 300,000 in California. Another 6.12% of the population (2.2 million Californians) suffer from early-stage AMD which puts them at high risk for developing geographic atrophy within 5 years. Currently there are some drugs available to help a certain portion of patients with the "wet" form of the disease, but there are no treatments for the "dry" or atrophic, form of the disease. We propose the use of transplants of healthy RPE cells into the eyes of patients with the atrophic form of AMD; these cells would be derived from the patients own skin or hair cells after inducing the production of pluripotent stem cells which could then be stimulated to become RPE cells. If successful, this approach would potentially provide a treatment for the leading cause of vision loss in Californians over the age of 65 with cells derived from their own tissue, avoiding potential complications associated with (1) repeated injections into the eye, (2) using cells from animals or other individuals and (3) deriving cells for transplant that have been exposed to animal cells or molecules and viral genetic material. Preserving vision in the elderly population not only would immensely improve the quality of life for these individuals, but it would also greatly facilitate their ability to function independently and productively.
Progress Report: 
  • The recent development of technologies capable of producing induced pluripotent stem (iPS) cells from adult somatic tissues may permit their use to generate autologous retinal pigment epithelium (RPE) grafts for the treatment of diseases like age-related macular degeneration. However, conventional reprogramming techniques are based on random genomic integration of four transcription factors with oncogenic potential. To minimize the risk of tumor formation, the use of iPS cells reprogrammed with a reduced number of these factors would be advantageous. We therefore evaluated the differentiation capacity of iPS cells generated from primary human epidermal keratinocytes by lentiviral transduction with only two or one factor (Oct4 and Klf4 or Oct4 only, respectively) and additional treatment with small molecules. Human iPS cells reprogrammed by conventional methods were used for comparison. Four factor-, two factor-, and one factor-derived iPS cells could be differentiated into cells that expressed RPE-specific markers (e.g., bestrophin, CRALBP, RPE65, tyrosinase). Moreover, these cells exhibited morphological and functional features characteristic of RPE cells such as formation of epithelial monolayers with intercellular tight junctions, homogenous polygonal morphology, pronounced pigmentation, phagocytosis of photoreceptor outer segments, and vectorial apical-to-basolateral fluid transport. Furthermore, we have demonstrated that the 1-factor iPSC-derived RPE cells, when injected into a rodent model of atrophic macular degeneration, could establish grafts of RPE and prevent the degeneration of photoreceptors (neurons) in this model. Thus, we demonstrate that human iPS cells generated by novel reprogramming techniques can be differentiated into cells with RPE-specific morphology, gene/protein expression and function. Compared to conventional iPS cells, these cells may be superior for clinical application due to the elimination of oncogenic reprogramming factors and, ultimately, retroviral transfection vectors.
  • The recent development of technologies capable of producing induced pluripotent stem (iPS) cells from adult somatic tissues may permit their use to generate autologous retinal pigment epithelium (RPE) grafts for the treatment of diseases like age-related macular degeneration. However, conventional reprogramming techniques are based on random genomic integration of four transcription factors with oncogenic potential. To minimize the risk of tumor formation, the use of iPS cells reprogrammed with a reduced number of these factors would be advantageous. We therefore evaluated the differentiation capacity of iPS cells generated from primary human epidermal keratinocytes by lentiviral transduction with only two or one factor (Oct4 and Klf4 or Oct4 only, respectively) and additional treatment with small molecules. Human iPS cells reprogrammed by conventional methods were used for comparison. Four factor-, two factor-, and one factor-derived iPS cells could be differentiated into cells that expressed RPE-specific markers (e.g., bestrophin, CRALBP, RPE65, tyrosinase). Moreover, these cells exhibited morphological and functional features characteristic of RPE cells such as formation of epithelial monolayers with intercellular tight junctions, homogenous polygonal morphology, pronounced pigmentation, phagocytosis of photoreceptor outer segments, and vectorial apical-to-basolateral fluid transport. Furthermore, we have demonstrated that the 1-factor iPSC-derived RPE cells, when injected into a rodent model of atrophic macular degeneration, could establish grafts of RPE and prevent the degeneration of photoreceptors (neurons) in this model. Thus, we demonstrate that human iPS cells generated by novel reprogramming techniques can be differentiated into cells with RPE-specific morphology, gene/protein expression and function. Compared to conventional iPS cells, these cells may be superior for clinical application due to the elimination of oncogenic reprogramming factors and, ultimately, retroviral transfection vectors.
  • The recent development of technologies capable of producing induced pluripotent stem (iPS) cells from adult somatic tissues may permit their use to generate autologous retinal pigment epithelium (RPE) grafts for the treatment of diseases like age-related macular degeneration. However, conventional reprogramming techniques are based on random genomic integration of four transcription factors with oncogenic potential. To minimize the risk of tumor formation, the use of iPS cells reprogrammed with a reduced number of these factors would be advantageous. We therefore evaluated the differentiation capacity of iPS cells generated from primary human epidermal keratinocytes by lentiviral transduction with only two or one factor (Oct4 and Klf4 or Oct4 only, respectively) and additional treatment with small molecules. Human iPS cells reprogrammed by conventional methods were used for comparison. Four factor-, two factor-, and one factorderived iPS cells could be differentiated into cells that expressed RPE-specific markers (e.g., bestrophin,CRALBP, RPE65, tyrosinase). Moreover, these cells exhibited morphological and functional features characteristic of RPE cells such as formation of epithelial monolayers with intercellular tight junctions, homogenous polygonal morphology, pronounced pigmentation, phagocytosis of photoreceptor outer segments, and vectorial apical-to-basolateral fluid transport. Furthermore, we have demonstrated that the 1-factor iPSC-derived RPE cells, when injected into a rodent model of atrophic macular degeneration, could establish grafts of RPE and prevent the degeneration of photoreceptors (neurons) in this model. Thus, we demonstrate that human iPS cells generated by novel reprogramming techniques can be differentiated into cells with RPE-specific morphology, gene/protein expression and function. Compared to conventional iPS cells, these cells may be superior for clinical application due to the elimination of oncogenic reprogramming factors and, ultimately, retroviral transfection vectors.
  • The recent development of technologies capable of producing induced pluripotent stem (iPS) cells from adult somatic tissues may permit their use to generate autologous retinal pigment epithelium (RPE) grafts for the treatment of diseases like age-related macular degeneration. However, conventional reprogramming techniques are based on random genomic integration of four transcription factors with oncogenic potential. To minimize the risk of tumor formation, the use of iPS cells reprogrammed with a reduced number of these factors would be advantageous. We therefore evaluated the differentiation capacity of iPS cells generated from primary human epidermal keratinocytes by lentiviral transduction with only two or one factor (Oct4 and Klf4 or Oct4 only, respectively) and additional treatment with small molecules. Human iPS cells reprogrammed by conventional methods were used for comparison. Four factor-, two factor-, and one factorderived iPS cells could be differentiated into cells that expressed RPE-specific markers (e.g., bestrophin,CRALBP, RPE65, tyrosinase). Moreover, these cells exhibited morphological and functional features characteristic of RPE cells such as formation of epithelial monolayers with intercellular tight junctions, homogenous polygonal morphology, pronounced pigmentation, phagocytosis of photoreceptor outer segments, and vectorial apical-to-basolateral fluid transport. Furthermore, we have demonstrated that the 1-factor iPSC-derived RPE cells, when injected into a rodent model of atrophic macular degeneration, could establish grafts of RPE and prevent the degeneration of photoreceptors (neurons) in this model. We have completed a study of the long-term effects of these cells injected into rodent eyes and observe continued trophic rescue effects and lack of any adverse events for up to two years post-injection. Thus, we demonstrate that human iPS cells generated by novel reprogramming techniques can be differentiated into cells with RPE-specific morphology, gene/protein expression and function. Compared to conventional iPS cells, these cells may be superior for clinical application due to the elimination of oncogenic reprogramming factors and, ultimately, retroviral transfection vectors.

Therapeutic potential of Retinal Pigment Epithelial cell lines derived from hES cells for retinal degeneration.

Funding Type: 
SEED Grant
Grant Number: 
RS1-00222
ICOC Funds Committed: 
$684 322
Disease Focus: 
Aging
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
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. Furthermore, retinitis pigmentosa is the leading cause of inherited blindness in younger people. Currently there are no cures for these diseases. 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 retina, and cooperate with other retinal cells to maintain normal visual function. The dysfunction and/or loss of these RPE cells play a critical role in the development of the previously described blinding diseases. We suggest that effective treatment of retinal degeneration could be achieved by the proper replacement of damaged RPE and retinal cells with healthy ones. However, lack of the reasonable supply of healthy human eye cells hampers the application of this therapeutic approach. Recent advances in knowledge and technology of embryonic stem cells brings new hope for the development of cell replacement treatment. Embryonic stem (ES) cells are capable of unlimited self-replication and production of different cell types. RPE cells derived from human ES cells (hES-RPE) are a potentially unlimited resource for the cell replacement approach. We hypothesize that the dysfunction and/or loss of RPE can be replenished and restored through the transplantation of functionally polarized RPE monolayers derived from human embryonic stem cells, and this transplantation can cure the retinal degeneration diseases caused by RPE dysfunction.We propose to: 1. Derive RPE cells from human ES cells; 2. Establish and characterize the functionally mature or polarized monolayer of hES-RPE cells that will be suitable for transplantation; 3. Rescue the retinal degeneration phenotype through the transplantation of functionally mature or polarized monolayer of hES-RPE cells in animal models. Our goal is to determine the feasibility of treating the retinal degeneration diseases caused by RPE dysfunction through the transplantation of a monolayer of polarized hES-RPE cell sheet. The knowledge and technology from our research can be used to develop new treatments for human retinal degeneration diseases.
Statement of Benefit to California: 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss or blindness among the elderly, and currently no cure for this disorder exists. Based on the fact that California is the most populated state, and that the population continues to age, it is estimated that over 450,000 of Californians will suffer from AMD with severe vision impairment by 2020. 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 and other retinal degenerative diseases through the transplantation of human embryonic stem cells that have been treated to differentiate into retinal pigment epithelial cells (RPE); the cells known to primarily degenerate or die in AMD. If our experimentation with RPE replacement therapy is successful in animal models, the knowledge and techniques can be quickly used to develop novel treatments for human diseases. Hundreds of thousands of Californians with AMD and other retinal degeneration diseases could benefit from our research for better quality of life with reduced morbidity. The California economy may significantly benefit from this work through potential reduced costs for health care, social welfare, and the loss of labor force.
Progress Report: 
  • 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 in the elderly. A layer of cells at the back of the eye called the retinal pigment epithelium (RPE), provides support, protection, and nutrition to the light sensitive retina, and cooperates with other retinal cells to maintain normal visual function. The dysfunction and/or loss of these RPE cells play a critical role in the development of dry AMD, the most common form of that disease. RPE cells derived from human ES cells (hES-RPE) are a potentially unlimited resource for cell replacement therapy.
  • During this grant period we were able to develop methods to reproducibly derive RPE cells from established human ES (hES) cell lines.
  • Normal RPE cells have a polarized appearance, meaning that they have specialized appearances and functions on the top (retinal facing) and bottom of the cells. We were then able to induce the hES-derived RPE to develop a polarized appearance very similar to that found in the normal eye. These cells had specialized characteristics that were remarkable similar to normal RPE and showed ability to function like normal RPE cells. We then developed sheets of hES-derived RPE on substrates that could be used for surgical implantation into animal eyes.
  • We then performed studies to establish appropriate animal models in which to test the ability of hES-derived RPE to prevent or slow retinal degeneration in animal models that have some features of human AMD. We were not able to use standard mouse models of AMD because mouse eyes are too small to perform the surgical implantation of polarized RPE. We first looked at a rabbit model of RPE degeneration induced by a toxin (sodium iodate). We were able to establish reproducible RPE degeneration in these animals but whenever we tried to implant hES-derived RPE under the retinas of these animals, the RPE cells did not survive. We believe that the toxin that was used to induce this model was being taken up by the transplanted cells resulting in their death. We then tested a genetic model of retinal degeneration in rats (RCS rat). We were able to demonstrate reproducible retinal degeneration in these animals. When we transplanted hES-derived RPE under the retinas of these animals, we were able to show that the RPE were indeed human in origin and that they were able to survive for at least several weeks after transplantation. Importantly, we were able to show that in the areas where hES-derived RPE were transplanted, there was less retinal degeneration than in the areas in which there was no transplantation or "sham" transplantation.
  • Thus, in conclusion, we were able to show (1) the reproducible culture of RPE cells from human ES cell lines, (2) that these hES-derived RPE had the appearance and functional characterisitics of human RPE and could be grown on substrates as sheets or polarized cells, and (3) that when these sheets of polarized hES-derived RPE were implanted under the retinal of rats with retinal degeneration, that they were able to survive and showed the ability to slow the progression of retinal degeneration in these animals.
  • The results of this study suggest that hES cells may be an unlimited source of RPE cells suitable for transplantation into eyes with retinal degeneration and that subretinal implantation of polarized hES-derived RPE may represent a novel therapy for dry AMD.

Development of Cellular Therapies for Retinal Disease

Funding Type: 
Research Leadership 2
Grant Number: 
LA1_C2-02086
ICOC Funds Committed: 
$4 880 116
Disease Focus: 
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
The long term goal of our research program is regeneration of the diseased eye. Age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa are leading causes of blindness for which there are no effective treatments for the majority of cases. Loss of vision is due to progressive degeneration of the photoreceptor cells, or loss of cells that support the photoreceptors, such as retinal pigment epithelial (RPE) cells or cells in the retinal blood vessels. The RPE is a pigmented cell layer that lies just behind the retinal and is necessary for photoreceptor survival. One possible strategy for treatment of these blinding diseases is to replace cells that are lost via transplantation. My work explores this approach, with the object of first identifying and characterizing sources of cells, determining the optimal parameters for transplantation, and investigating molecular, cellular and behavioral events that occur upon transplantation in animal models of retinal degeneration. In the case of age-related macular degeneration, there is a solid body of evidence that RPE cell loss is often an early event in disease progression. We have shown that RPE can be derived from human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC), and they can rescue vision in rodent and pig models of retinal dystrophy. We have joined forces with interdisciplinary teams in the UK and California to transition this work to the clinic, using RPE derived from hESC. We will also investigate other forms of RPE-based eye disease by generating iPSC from patients, differentiating them to RPE, and analyzing function. Small molecules that are candidate drugs will then be screened for functional rescue. In the case of diabetic retinopathy, we are investigating a strategy to used hESC-derived cells to repair blood vessels. Finally, in retinitis pigmentosa, we will pursue a possible route to replace photoreceptors by converting the surviving retinal ganglion cells into light sensing cells. The aim of the proposed studies is to provide foundational knowledge that will enable and guide further translation of cellular therapies to improve vision in patients.
Statement of Benefit to California: 
Age-related macular degeneration (AMD), retinitis pigmentosa (RP) and diabetic retinopathy are leading causes of vision loss and blindness. Because California is the most populous state in the nation, and because the elderly constitute a greater percentage of its population, it is estimated that over 450,000 of Californians will suffer from AMD with severe vision impairment by 2020, leading to huge costs. Diabetes continues to be a major health concern, with vision loss a common outcome. Moreover, the devastating consequences of vision deficits 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. Clearly, there is a need for better treatments. In these diseases, loss of vision is due to progressive degeneration of the light sensitive photoreceptor cells of the eye or defects in the supporting cells of the eye, including the retinal pigmented epithelium (RPE). There is now a solid body of evidence that suggests that RPE degeneration is the first step in AMD. There is no cure for these conditions at present, although studies of model experimental animals, mostly rats and mice, suggest several possible routes to therapy. One of these involves the transplantation of cells to slow the degeneration of photoreceptors by replacing key support cells lost during degeneration. My work explores this approach with the object of first identifying and characterizing sources of ocular cells, determining the optimal parameters for transplantation, and identifying molecular and cellular and behavioral events that occur upon transplantation in animal models of retinal degeneration. One source of cells for transplantation is ocular cells derived from human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC). We have shown that ocular cells, especially RPE, can be derived from both hESC and iPSC, and they can rescue visual function in rodent models of retinal dystrophy. We have shown that RPE can be derived from both hESC and iPSC, and they can rescue visual function in rodent models of retinal dystrophy. We have teamed up with an interdisciplinary disease team of stem cell biologists, materials chemists, neuroscientists, and retinal surgeons to transition this work towards clinical application for AMD, using hESC to produce RPE. Other research aims are to generate specific blood vessel cells from stem cells to replenish the retinal blood vessels in diabetic retinopathy, to generate new photosensitive cells to restore vision, and to use iPSC derived from patients to understand retinal disease and identify novel treatments. California patients with vision loss will benefit greatly from the studies proposed.
Progress Report: 
  • The goal for the first year was to establish a totally new laboratory from the ground up at the recently opened new UC Santa Barbara Center for Stem Cell Biology and Engineering funded by CIRM. This involved equipping the whole laboratory from small to large equipment items. This was made possible by the recruitment of three excellent scientists: a senior scientist, a research technician and a PhD student. This enabled the laboratory to quickly get established and running some initial experiments to ensure processes were working. We have run a number of preliminary experiments the results of which will be presented at conference later this year. The goal of the initial experiments was to establish techniques to improve cell transplantation for eye diseases.
  • The foundation of this project is built on the premise of cell therapies for age-related macular degeneration (AMD). AMD is a disease of failed and eventually aberrant wound repair. In its early phase, it is characterized by the formation and accumulation of debris in the back of the eye that can act as barriers to normal function and lead to activation of an immune response. While the nature of the insult that initiates this response is not fully understood, it may in part be due to cumulative wear and tear that results in oxidative or physical damage to eye. Whatever the origin, the response only serves to cause further damage and disease progression. Eventually, a tipping point is reached that triggers a switch that leads to the transition to the advanced forms of AMD characterized by cell death and and scaring. The aim of the second year is to understand this wound response and change using stem cell based models.

Stem cell based treatment strategy for Age-related Macular Degeneration (AMD)

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01444
ICOC Funds Committed: 
$18 904 916
Disease Focus: 
Vision Loss
Collaborative Funder: 
UK
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
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.
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 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.
Progress Report: 
  • 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 retinal degenerative disease in the elderly. AMD is a progressive ocular disease of the part of the retina at the back of the eye, 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 photoreceptors in the retina. 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. RPE cells derived from human embryonic stem cells (hESC) are a potentially unlimited and robust source for regenerating RPE (hESC-RPE).
  • During the first year of our Disease Team Grant we have assembled a closely working team of interdisciplinary scientists and physician scientists at the University of Southern California (USC), Doheny Eye Institute (DEI), University of California Santa Barbara (UCSB), California Institute of Technology (Caltech), and City of Hope (COH). Our scientists work and meet together frequently to discuss progress and we have had 2 highly successful full-day retreats; one at USC and one at UCSB.
  • We are on track for each of the Year 1 proposed milestones. During the first year we have made a decision on final selection of hESC line; and have developed protocols for the generation and molecular and functional characterization of hESC-RPE and are transferring these protocols to our manufacturing and regulatory partners at City of Hope. COH has had onsite visits to learn protocols at UCSB and USC and we have had a day-long meeting at COH to further refine protocols and procedures. In collaboration with Caltech we have developed a non-biodegradable substrate on which these cells are grown and where they develop characteristics of mature RPE cells. Specialized surgical instruments have been developed at DEI and Caltech to implant the hESC cells grown on substrate under the retina. We have utilized sophisticated instrumentation to image the retina in live animals and have used these instruments to follow rats with progressive retinal degeneration before and after implantation of the hESC. We have demonstrated that hESC rescue the degeneration and integrate well into the host retina. Sections of these retinas are evaluated histologically at the microscopic level using sophisticated quantitative imaging techniques.
  • 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 ultimate goal is to submit an Investigational New Drug (IND) Application to the Food and Drug Administration (FDA) by the end of the 4th year of the grant 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 a devastating disease that can lead to severe vision impairment and blindness. Vision loss in AMD usually is after age 55 and affects almost 2 million Americans.
  • Vision is initiated by light striking and activating specific cells called photoreceptor cells of the neural retina within the eye. There is a small, specialized region in the central portion of the retina called the macula that is particularly important for central, sharp and color vision. It has a high percentage of photoreceptor cells called "cone cells" and it is this region that is most affected by AMD. Thus, with cone cell degeneration in AMD, a person loses their central, sharp vision with color vision affected as well.
  • In the normal retina, photoreceptor cells are supported metabolically and structurally by a thin layer of cells next to them called Retinal Pigment Epithelial (RPE)Cells. Without these RPE cells, photoreceptor cells quickly degenerate and die. In AMD, it is thought that dysfunction of RPE cells is an early and critical sign of AMD. Thus, replacing dead or dying RPE cells in AMD could be a way to slow the disease process and even improve vision.
  • Our CIRM disease team grant which we call The California Project to Cure Blindness aims to treat AMD through replacement of these dysfunctional RPE cells with fresh RPE cells that will then keep photoreceptor cells alive and functioning. Because only very few RPE cells are present in a human eye, direct RPE transplantation would be very difficult so we rely on the use of human embryonic stem cells (hESCs). Through the work in our CIRM funded disease team grant we have been able to use a particular stem cell line and differentiate into adult-like RPE cells that exhibit many characteristics of normal mature human RPE cells. We believe that implanting these hESCs within the eye next to the retina could be of benefit in AMD in saving the photoreceptors.
  • Our technique is to not only implant the hESC derived RPE cells in the eye but to place them on a special ultrathin substrate platform that will maintain them in proper orientation next to the retina. Moreover, implantation can be done with hESC cells that had been allowed to differentiate in tissue culture prior to implantation, insuring that the implanted cells indeed express the characteristics of mature, functional RPE cells.
  • In this last year, substantial progress has been made in progressing to our goal of replenishing RPE cells in the AMD retina and restoring vision. First, a specific hESC line has been identified that will differentiate into cells that have many of the morphological and biochemical characteristics of normal adult RPE cells. Second, an appropriate material has been found that can act as a substratum (platform) that will support the RPE cells and allow them to function in a normal manner. Third, we have begun to demonstrated the safety of our procedure as well as its efficacy in slowing vision loss in a rodent model of retina degeneration. Fourth, we also have developed unique surgical techniques that will allow us to safely and effectively place the cells in the animal and ultimately human eyes.
  • In parallel to these basic studies, we are advancing our strategies that will let us treat human patients with AMD. Clinical protocols are being established that will be submitted to the US FDA to gain their approval in order to start phase 1 (early) Clinical Trial. In summary, our CIRM grant has allowed us to develop a procedure that should let us treat severe vision loss in AMD. Already, data at 6 months in animal studies has demonstrated the safety of the technique as well as the restoration of functional vision in a model system. Hopefully, this will lead us to a successful human clinical trial with sight restoration in currently untreatable cases of dry AMD.
  • Age-Related Macular Degeneration (AMD) is a devastating disease that can lead to severe vision impairment and blindness. Vision loss in AMD usually is after age 55 and affects almost 2 million Americans.
  • Vision is initiated by light striking and activating specific cells called photoreceptor cells of the neural retina within the eye. There is a small, specialized region in the central portion of the retina called the macula that is particularly important for central, sharp and color vision. It has a high percentage of photoreceptor cells called "cone cells" and it is this region that is most affected by AMD. Thus, with cone cell degeneration in AMD, a person loses their central, sharp vision with color vision affected as well.
  • In the normal retina, photoreceptor cells are supported metabolically and structurally by a thin layer of cells next to them called Retinal Pigment Epithelial (RPE)Cells. Without these RPE cells, photoreceptor cells quickly degenerate and die. In AMD, it is thought that dysfunction of RPE cells is an early and critical sign of AMD. Thus, replacing dead or dying RPE cells in AMD could be a way to slow the disease process and even improve vision.
  • Our CIRM disease team grant which we call The California Project to Cure Blindness aims to treat AMD through replacement of these dysfunctional RPE cells with fresh RPE cells that will then keep photoreceptor cells alive and functioning. Because only very few RPE cells are present in a human eye, direct RPE transplantation would be very difficult so we rely on the use of human embryonic stem cells (hESCs). Through the work in our CIRM funded disease team grant we have been able to use a particular stem cell line and differentiate into adult-like RPE cells that exhibit many characteristics of normal mature human RPE cells. We believe that implanting these hESCs within the eye next to the retina could be of benefit in AMD in saving the photoreceptors.
  • Our technique is to not only implant the hESC derived RPE cells in the eye but to place them on a special ultrathin substrate platform that will maintain them in proper orientation next to the retina. Moreover, implantation can be done with hESC cells that had been allowed to differentiate in tissue culture prior to implantation, insuring that the implanted cells indeed express the characteristics of mature, functional RPE cells.
  • In this last year, substantial progress has been made in progressing to our goal of replenishing RPE cells in the AMD retina and restoring vision. First, a specific hESC line has been identified that will differentiate into cells that have many of the morphological and biochemical characteristics of normal adult RPE cells. Second, an appropriate material has been found that can act as a substratum (platform) that will support the RPE cells and allow them to function in a normal manner. Third, we have begun to demonstrated the safety of our procedure as well as its efficacy in slowing vision loss in a rodent model of retina degeneration. Fourth, we also have developed unique surgical techniques that will allow us to safely and effectively place the cells in the animal and ultimately human eyes.
  • In parallel to these basic studies, we are advancing our strategies that will let us treat human patients with AMD. Clinical protocols are being established that will be submitted to the US FDA to gain their approval in order to start phase 1 (early) Clinical Trial. In summary, our CIRM grant has allowed us to develop a procedure that should let us treat severe vision loss in AMD. Already, data at 6 months in animal studies has demonstrated the safety of the technique as well as the restoration of functional vision in a model system. Hopefully, this will lead us to a successful human clinical trial with sight restoration in currently untreatable cases of dry AMD.
  • Age-Related Macular Degeneration (AMD) is a devastating disease that can lead to severe vision impairment and blindness. Vision loss in AMD usually is after age 55 and affects almost 2 million Americans.
  • Vision is initiated by light striking and activating specific cells called photoreceptor cells of the neural retina within the eye. There is a small, specialized region in the central portion of the retina called the macula that is particularly important for central, sharp and color vision. It has a high percentage of photoreceptor cells called "cone cells" and it is this region that is most affected by AMD. Thus, with cone cell degeneration in AMD, a person loses their central, sharp vision with color vision affected as well.
  • In the normal retina, photoreceptor cells are supported metabolically and structurally by a thin layer of cells next to them called Retinal Pigment Epithelial (RPE)Cells. Without these RPE cells, photoreceptor cells quickly degenerate and die. In AMD, it is thought that dysfunction of RPE cells is an early and critical sign of AMD. Thus, replacing dead or dying RPE cells in AMD could be a way to slow the disease process and even improve vision.
  • Our CIRM disease team grant which we call The California Project to Cure Blindness aims to treat AMD through replacement of these dysfunctional RPE cells with fresh RPE cells that will then keep photoreceptor cells alive and functioning. Because only very few RPE cells are present in a human eye, direct RPE transplantation would be very difficult so we rely on the use of human embryonic stem cells (hESCs). Through the work in our CIRM funded disease team grant we have been able to use a particular stem cell line and differentiate into adult-like RPE cells that exhibit many characteristics of normal mature human RPE cells. We believe that implanting these hESCs within the eye next to the retina could be of benefit in AMD in saving the photoreceptors.
  • Our technique is to not only implant the hESC derived RPE cells in the eye but to place them on a special ultrathin substrate platform that will maintain them in proper orientation next to the retina. Moreover, implantation can be done with hESC cells that had been allowed to differentiate in tissue culture prior to implantation, insuring that the implanted cells indeed express the characteristics of mature, functional RPE cells.
  • In this last year, substantial progress has been made in progressing to our goal of replenishing RPE cells in the AMD retina and restoring vision. First, a specific hESC line has been identified that will differentiate into cells that have many of the morphological and biochemical characteristics of normal adult RPE cells. Second, an appropriate material has been found that can act as a substratum (platform) that will support the RPE cells and allow them to function in a normal manner. Third, we have begun to demonstrated the safety of our procedure as well as its efficacy in slowing vision loss in a rodent model of retina degeneration. Fourth, we also have developed unique surgical techniques that will allow us to safely and effectively place the cells in the animal and ultimately human eyes.
  • In parallel to these basic studies, we are advancing our strategies that will let us treat human patients with AMD. Clinical protocols are being established that will be submitted to the US FDA to gain their approval in order to start phase 1 (early) Clinical Trial. In summary, our CIRM grant has allowed us to develop a procedure that should let us treat severe vision loss in AMD. Already, data at 6 months in animal studies has demonstrated the safety of the technique as well as the restoration of functional vision in a model system. Hopefully, this will lead us to a successful human clinical trial with sight restoration in currently untreatable cases of dry AMD.

Phase 1 Safety Assessment of CPCB-RPE1, hESC-derived RPE Cell Coated Parylene Membrane Implants, in Patients with Advanced Dry Age Related Macular Degeneration

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07438
ICOC Funds Committed: 
$18 922 665
Disease Focus: 
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
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 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), provides support, protection, and nutrition to the light sensitive cells of the retina; the photoreceptors. The dysfunction and/or loss of these RPE cells is believed to play a critical role in the subsequent death of photoreceptors and resulting loss of vision in AMD. Hence, if RPE cells can be restored, it may be possible to prevent or delay progressive vision loss in patients with AMD. We are developing a therapy to replace RPE cells in patients with a form of AMD known as geographic atrophy. The RPE cells are delivered on a synthetic membrane, just as normal RPE cells in the eye are arranged as a thin layer of cells on a substrate known as the Bruch’s membrane. We have made excellent progress in the current grant period funded by CIRM and are on track to file to an investigational new drug application to the FDA to start the phase 1 human study. We have also shown that our approach of delivering the RPE as a sheet into diseased animal eyes has a much better chance of restoring retinal function than if these cells were injected as a suspension. In this current grant from CIRM, we are seeking to translate this preclinical work and to test this product in a Phase I clinical trial in patients with geographic atrophy.
Statement of Benefit to California: 
Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among the elderly. It is estimated that over 1.75 million individuals in the US suffer from advanced AMD, and that this number will grow to nearly 3 million by 2020. Based on the demographics of California and the incidence rates of AMD among various age groups, it is anticipated that more than 400,000 Californians will develop advanced forms of AMD over the next 15 years. Although VEGF inhibitors such as Lucentis and Eylea provide therapeutic options for the wet form of AMD, no approved therapies currently exist for the advanced form of dry AMD, geographic atrophy, which is estimated to affect more than 100,000 Californians today, with another 160,000 new cases in California expected in the next 15 years. 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 patients, resulting in substantial quality of life and economic impacts to many Californians. One health economics analysis estimated the total GDP from dry AMD in the United States to be more than $24 billion annually. Given that California accounts for more than 12% of US GDP, this analysis can be extrapolated to estimate that total GDP loss due to dry AMD in California is likely nearly $3 billion annually. In the proposed project, phase I clinical testing of an implant composed of an ultrathin membrane coated with human embryonic stem cell-derived retinal pigment epithelial cells (RPE), one of the key cell types known to primarily degenerate or die in AMD, will begin in patients with advanced AMD. This project has been developed in California and clinical testing will begin in California. This project will benefit the state of California by providing treatment options for the hundreds of thousands of Californians with dry AMD, providing support for the further development of a therapy originally developed with California, and creating jobs in California by enabling the formation a new California-based start-up to further develop this product.

Retinal progenitor cells for treatment of retinitis pigmentosa

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05739
ICOC Funds Committed: 
$17 306 668
Disease Focus: 
Vision Loss
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
The targeted disease is retinitis pigmentosa (RP), a severe form of blindness that often runs in families, but other times arises spontaneously from genetic errors. This disease is not overly common, yet represents an attainable near term target for stem cell therapy for a number of reasons: 1) RP destroys the light detecting cells of the retina in the back of the eye, yet generally leaves the rest of the visual system and body unharmed, so the clinical goal is circumscribed; 2) RP is prototypical of degenerations of the nervous system, so a cure for this less common disease would accelerate progress towards new therapies for a range of more familiar conditions; 3) scientific research has shown that degenerating rods and cones can be saved in animals by transplanting particular types of stem cells, thus the scientific feasibility of treating RP in this way has already been established in principle. The therapeutic approach to be championed here is to save the light sensing cells of the eye (rod and cone photoreceptors) in people going blind using a type of stem cell obtained from the immature retina, but not from early embryos. These particular stem cells from the retina, known as progenitor cells, are capable of saving photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at producing new rod photoreceptors and this provides another more sustained pathway by which they preserve the crucial cone photoreceptors. In addition, there is evidence that the stem cells themselves might become functional photoreceptors and thereby stabilize the retina by directly replacing the dying cells in the patient’s eye. Thus, transplanted stem cells could treat the targeted disease of RP in multiple ways simultaneously. Importantly, there are a host of reasons why clinical trials in the eye are easier and safer than most locations in the body. The eye is an important proving ground for stem cell-based therapies and provides a stepping stone to many otherwise incurable diseases of the brain and spinal cord. As part of the current project, our cell type of interest will be grow under conditions ensuring pharmaceutical standards are met. The resulting cells will be tested in animals for safety and to make certain that they are therapeutically potent. An application will be made to the FDA seeking approval for the use of these cells in early clinical trials. Following approval, a small number of patients with severe RP will be injected with cells in their worse-seeing eye and followed clinically for a specified period of time to determine the safety and effectiveness of the treatment.
Statement of Benefit to California: 
Benefits to the state of California and its citizens are both direct and indirect. The direct benefit is medical in that there is currently no cure or established treatment for the individuals and families that suffer from the dreadful hereditary blindness known as retinitis pigmentosa. In addition, there are many people in California and throughout the world that suffer from degenerative diseases of the retina, such as age-related macular degeneration (AMD), and the central nervous system that could benefit from further development and alternate applications of the type of stem cell therapy proposed in the current application. The rapid progress into the clinic that could be achieved via this proposal would help legitimize the use of stem cells for previously incurable diseases and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other conditions. In so doing there would be an indirect benefit to California by making our state a focal point for stem cell breakthroughs. This would increase medical capabilities, strengthen the state’s educational system, and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues. In the current economic situation, the citizens of the state are looking for a return on their investment in stem cell research. The leadership for the state is looking for a novel technology to reinvigorate the economy, provide desirable jobs, and reaffirm the flagship image of California. The project presented in this application has a real chance of provide that sort of spark.
Progress Report: 
  • Retinitis pigmentosa (RP) is a severe form of blindness that often runs in families, but other times arises spontaneously or from recessive genetic errors. This disease is rare, yet represents an attainable near term target for stem cell therapy for a number of reasons: 1) RP destroys the light detecting cells of the retina in the back of the eye, yet generally leaves the rest of the visual system and body unharmed, so the clinical goal is circumscribed; 2) RP is prototypical of degenerations of the nervous system, so a cure for this less common disease would accelerate progress towards new therapies for a range of more familiar conditions; 3) scientific research has shown that degenerating rods and cones can be saved in animals by transplanting particular types of stem cells, thus the scientific feasibility of treating RP in this way has already been established in principle. The therapeutic approach pursued by our team is to save the light sensing cells of the eye (rod and cone photoreceptors) by transplanting a type of stem cell known as a progenitor cell. These cells are capable of saving photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at producing new rod photoreceptors and this provides another more sustained pathway by which they preserve the crucial cone photoreceptors. In addition, there is evidence that the stem cells themselves might become functional photoreceptors and thereby stabilize the retina by directly replacing the dying cells in the patient’s eye. Thus, transplanted stem cells could treat the targeted disease of RP in multiple ways simultaneously. Importantly, there are a host of reasons why clinical trials in the eye are easier and safer than most locations in the body. The eye is therefore an important proving ground for stem cell-based therapies and provides a steppingstone to many otherwise incurable diseases of the brain and spinal cord.
  • As part of the current project, our cell type of interest has now been manufactured under specific conditions ensuring that pharmaceutical standards are met (Good Manufacturing Practice, GMP). The resulting GMP cells have been tested in the laboratory to verify that they are free from microbial contamination and chromosomal defects. The cells are currently being tested in animals for safety and to make certain that they are therapeutically potent. When this testing is completed, an application will be made to the FDA seeking approval for the use of these cells in early clinical trials. Following approval, a small number of patients with severe RP will be injected with cells in their worse-seeing eye and followed clinically for a specified period of time to determine the safety and effectiveness of the treatment.

The CIRM Human Pluripotent Stem Cell Biorepository – A Resource for Safe Storage and Distribution of High Quality iPSCs

Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.
Statement of Benefit to California: 
The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

Restoring vision by sheet transplants of retinal progenitors and retinal pigment epithelium (RPE) derived from human embryonic stem cells (hESCs)

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06648
ICOC Funds Committed: 
$4 318 439
Disease Focus: 
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
There is currently no effective treatment to restore or improve vision for patients suffering from incurable blinding diseases such as dry age-related macular degeneration and retinitis pigmentosa, which need both new photoreceptors and retinal pigment epithelium. However, a unique method to transplant fetal retinal progenitor sheets together with its supporting retinal pigment epithelium (RPE) has been shown to improve vision in animal models of retinal degeneration and in patients. Differentiation of human embryonic stem cells (hESCs) into sheets of retinal progenitor tissue that contain photoreceptor progenitors and RPE cells could create an unlimited supply of donor tissue. Our lab has generated retinal progenitor tissue from hESCs in 3-D constructs (“layers”), and a new immunodeficient model of retinal degeneration. Recently, several laboratories have shown that hESCs can “self-assembly” into early stages of eye development and develop into laminated structures. The hypothesis of the proposed project then is that hESCs can be consistently differentiated into sheets of retinal tissue, which can restore visual responses after transplantation to a new immunodeficient rat model of retinal degeneration that does not reject human cells. In the final year, we will standardize methods to increase the production of these sheets in a way that complies to good manufacturing practice. This project will ultimately help to restore vision in patients suffering from retinal diseases.
Statement of Benefit to California: 
Retinal diseases reduce the quality of life of patients who suffer from vision loss and at significant cost to the health care system. Age-related macular degeneration (AMD) destroys the central vision and is the most common cause of blindness among people over 65. In 2010, AMD affected 2.1 % of the general population which means 2.1 million in the U.S. and about 240,000 in California, with these numbers projected to grow to 5 million (in the U.S.) in 2050 as the population ages. Ca. 20-35% of AMD cases develop irreversible geographic atrophy with local loss of RPE and photoreceptors in the macula. Another incurable disease, retinitis pigmentosa (RP) which is inherited (1:3500) and occurs in younger people, affects the light-sensing photoreceptors first, but also the supporting RPE layer beneath the retina following photoreceptor degeneration. Thus, both AMD and RP patients will need both new RPE and photoreceptors. The proposed replacement therapy is the only one that targets more mature disease stages of both AMD and RP, for which no other therapy exists. An effective treatment will keep afflicted individuals productive, enhance State tax revenues and defray the healthcare cost burden to taxpayers. It will also lead to robust industry developments in the fields of clinical transplantation, drug screening, and predictive toxicology, effectively leading to job creation and tax benefits to the State as a result of consumption of research and clinical goods and services.

Generation of fibroblast cell lines in patients with common blinding eye diseases

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06601
ICOC Funds Committed: 
$1 034 452
Disease Focus: 
Vision Loss
oldStatus: 
Active
Public Abstract: 
Age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), and proliferative diabetic retinopathy (PDR) are the major causes of irreversible vision loss worldwide. Although the exact causes and mechanisms of these diseases are not completely understood, it is known that genetic and environmental factors contribute to the development of these diseases. Recent scientific advances have enabled the reprogramming of already-differentiated tissues such as skin cells back to cells called induced pluripotent stem cells (iPSCs). iPSCs have the potential to be programmed into different cells in the eye, which are lost in degeneration. We therefore propose to obtain skin biopsies from patients with the above mentioned eye disease. The goals are to provide samples from a well-characterized patient population whose members exhibit the target eye diseases. Although there are animal models of eye diseases, retinal cells derived from iPSC will provide a better and faster way for disease modeling in the dish, novel tools for drug screening. The iPSC-derived retinal cells can also be used to replace degenerated or damaged retinal cells to restore vision for millions of patients, such as retinal pigment epithelium (RPE) cells to treat AMD and retinal ganglion cells to treat glaucoma.
Statement of Benefit to California: 
Blindness or impaired vision affects 3.3 million Americans ages 40 and over, or one in 28, according to a study sponsored by NIH. This figure is projected to reach 5.5 million by the year 2020. The rate of low vision and blindness increases significantly with age, particularly in people over age 65. California has the largest population in the United States. With the aging of the population, the number of Californians with age-related eye diseases is increasing, and vision loss is expected to remain a major public health and societal economic concern in addition to its substantial effect on individual living quality. Our proposed study of tissue collection from patients with major eye diseases will provide new means and materials to understand mechanisms of susceptibility to ocular diseases. It is innovative and promises a number of unique contributions to the field of regenerative medicine. By integration of clinical and genome-wide association datasets, we will be able to perform a comprehensive and coordinated study designed to identify and understand the complex interplay of genetic, developmental and environmental factors, and their contributions to the development and progression of major eye disorders. This should open a new avenue for future functional studies and could eventually help facilitate the prediction, development of improved treatment, and prevention of devastating blindness-causing diseases.

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