Vision Loss

Coding Dimension ID: 
325
Coding Dimension path name: 
Vision Loss
Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
Investigator: 
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Liver Disease
Epilepsy
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.

Progress Report: 
  • The California Institute for Regenerative Medicine (CIRM) Human Pluripotent Stem Cell Biorepository is operated by the Coriell Institute for Medical Research and is a critical component of the CIRM Human Stem Cell Initiative. The overall goal of this initiative is to generate, for world-wide use by non-profit and for-profit entities, high quality, disease-specific induced pluripotent stem cells (iPSCs). These cells are derived from existing tissues such as blood or skin, and are genetically manipulated in the laboratory to change into cells that resemble embryonic stem cells. iPSCs can be grown indefinitely in the Petri dish and have the remarkable capability to be converted into most of the major cell types in the body including neurons, heart cells, and liver cells. This ability makes iPSCs an exceptional resource for disease modeling as well as for drug screening. The expectation is that these cells will be a major benefit to the process for understanding prevalent, genetically complex diseases and in developing innovative therapeutics.
  • The Coriell CIRM iPSC Biorepository, located at the Buck Institute for Research on Aging in Novato, CA, is funded through a competitive grant award to Coriell from CIRM and is managed by Mr. Matt Self under the supervision of the Program Director, Dr. Steven Madore, Director of Molecular Biology at Coriell. The Biorepository will receive biospecimens consisting of peripheral blood mononuclear cells (PBMCs) and skin biopsies obtained from donors recruited by seven Tissue Collector grant awardees. These biospecimens will serve as the starting material for iPSC derivation by Cellular Dynamics, Inc (CDI). Under a contractual agreement with Coriell, CDI will expand each iPSC line to generate sufficient aliquots of high quality cryopreserved cells for distribution via the Coriell on-line catalogue. Aliquots of frozen cell lines and iPSCs will be stored in liquid nitrogen vapor in storage units at the Buck Institute with back-up aliquots stored in a safe off-site location.
  • Renovation and construction of the Biorepository began at the Buck Institute in late January. The Biorepository Manger was hired March 1 and after installation of cryogenic storage vessels and alarm validation, the first biospecimens were received on April 30, 2014. Additionally, Coriell has developed a Clinical Information Management System (CIMS) for storing all clinical and demographic data associated with enrolled subjects. Tissue Collectors utilize CIMS via a web interface to upload and edit the subject demographic and clinical information that will ultimately be made available, along with the iPSCs, via Coriell’s on-line catalogue
  • As of November 1 specimens representing a total of 725 unique individuals have been received at the Biorepository. These samples include PBMCs obtained from 550 unique individuals, skin biopsies from 72 unique individuals, and 103 primary dermal fibroblast cultures previously prepared in the laboratories of the CIRM Tissue Collectors. A total of 280 biospecimen samples have been delivered to CDI for the purpose of iPSC derivation. The Biorepository is anticipating delivery of the first batches of iPSCs for distribution in early 2015. These lines, along with the associated clinical data, will become available to scientists via the on-line Coriell catalogue. The CIRM Coriell iPSC Biorepository will ensure safe long-term storage and distribution of high quality iPSCs.
Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
Investigator: 
Type: 
PI
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
Liver Disease
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.

Progress Report: 
  • First year progress on grant ID1-06557, " Generation and Characterization of High-Quality, Footprint-Free Human Induced Pluripotent Stem Cell (iPSC) Lines From 3000 Donors to Investigate Multigenic Disease" has met all agreed-upon milestones. In particular, Cellular Dynamics International (CDI) has taken lease to approximately 5000 square feet of lab space at the Buck Institute for Research on Aging in Novato, CA. The majority of this space is located within the new CIRM-funded Stem Cell Research Building at the Buck Institute and was extensively reconfigured to meet the specific needs of this grant. All equipment, including tissue culture safety cabinets and incubators, liquid-handling robotics, and QC instrumentation have been installed and qualified. A total of 16 scientists have been hired and trained (13 in Production and 3 in Quality) and more than 20 Standard Operating Procedures (SOPs) have been developed and approved specifically for this project. These SOPs serve to govern the daily activities of the Production and Quality staff and help ensure consistency and quality throughout the iPSC derivation and characterization process. In addition, a Laboratory Information Management System (LIMS) had to be developed to handle the large amount of data generated by this project and to track all samples from start to finish. The first and most important phase of this LIMS project has been completed; additional functionalities will likely be added to the LIMS during the next year, but completion of phase 1 will allow us to enter full production mode on schedule in the first quarter of year 2. Procedures for the shipping, infectious disease testing, and processing of donor samples were successfully implemented with the seven Tissue Collectors. To date, over 700 samples have been received from these Tissue Collectors and derivation of the first 50 patient-derived iPSC lines has been completed on schedule. These cells have been banked in the Coriell BioRepository, also located at the Buck Institute. The first Distribution Banks will be available for commercial release during year 2.
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01444
Investigator: 
Type: 
PI
Type: 
Co-PI
Type: 
Co-PI
Type: 
Partner-PI
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.
  • 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 which we call “The California Project to Cure Blindness (CPCB)” 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 access to adult RPE cells is extremely limited, we produce RPE cells from human embryonic stem cells (hESCs). Through the work conducted by the CPCB team, we have been able to produce adult-like RPE cells that exhibit many characteristics of normal mature human RPE cells. These RPE cells are cultured on an ultrathin membrane that provides the RPE cells that proper signals for survival, polarization and function of the cells. The implant which includes the RPE cells and the membrane is delivered under the retina to support photoreceptors as a permanent implant.
  • In this last year, substantial progress has been made towards our goal of replenishing RPE cells in the AMD retina and restoring vision. During the last year, we have demonstrated the activity of the CPCB implant in slowing vision loss in a rodent model of retina degeneration. These studies, along with experiments performed in swine, showed that the implant could be safely delivered and maintained under the retina.
  • In parallel to these basic studies, we have advanced our strategies that will let us treat patients with AMD. A clinical protocol has been prepared and was submitted to the US FDA to gain their approval in order to start a Phase 1/2b 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. The data in animal studies has demonstrated the safety of the technique as well as the restoration of some functional vision in a model system. Hopefully, this will lead us to successful human clinical trials with sight restoration in currently untreatable cases of dry AMD.
Funding Type: 
Early Translational II
Grant Number: 
TR2-01768-B
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$3 054 024
Disease Focus: 
Vision Loss
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 

Over 3.2 million people worldwide are bilateral blind from corneal diseases. Limbal stem cell deficiency (LSCD) has been recognized as a major cause, either primary or secondary, of significant visual loss and blindness in many common corneal disorders.
A healthy, transparent ocular surface is made up of non-keratinized, stratified squamous epithelium that is highly differentiated. The corneal epithelium is constantly renewed and maintained by the corneal epithelial stem cells, or limbal stem cells (LSCs) that are presumed to reside at the limbus, the junction between the cornea and conjunctiva. When the LSCs are deficient and unable to repopulate the corneal surface, the cornea surface will become opaque. Corneal transplant can’t survive and is contraindicated in LSCD.
LSC transplantation, in the form of keratolimbal allograft to restore a transparent corneal surface, has been the main therapy in the United States. The 5-year survival of these allografts is about 30%, largely due to immune rejection. Transplantation of autologous limbal epithelial stem cells that have been expanded on tissue culture has successfully restored vision and revolutionized the patient specific stem-cell based therapy as recently reported by an Italian LSC transplant team. They have achieved a 68% success rate during a mean follow up time of 3 years. The expansion process requires mouse 3T3 feeder cells to grow a sufficient amount of stem cells for transplantation. To reduce cross-contamination from animal products, LSCs that are expanded in a xenobiotic-free culture system has been established; however, the 3-year survival rate of these cells after transplantation is 50% and only 30% survive at 5 year, suggestive of inefficient expansion without the mouse feeders. Therefore, new cell engineering methods that can efficiently expand and regenerate autologous LSCs in a xenobiotic-free system are dearly needed to achieve acceptable clinical outcome and offer stem-cell based therapy to patients with this devastating blinding diseases in the United States.
The first goal of this proposed translational research is to establish a xenobiotic-free culture system by replacing the mouse feeder cells with a human feeder system to expand sufficient amount of LSCs for transplantation. This will allow immediate initiation of clinical trial. We will then further optimized the expansion efficiency by modulating the Wnt and Notch signaling pathways based on our findings that Wnt and Notch signaling regulate the proliferation and differentiation of corneal epithelial cells. In parallel, transdifferentiation of human skin epithelial stem cells to corneal epithelial cells will be induced using a similar approach. The ability and safety of these regenerated human corneal epithelial stem cells to reconstruct the ocular surface will be tested in a LSCD animal model. The results of this proposed study will pave the way for preclinical development of this novel cell engineering technique.

Statement of Benefit to California: 

This proposal is to develop a stem-cell based transplantation therapy for treating a blinding corneal disorder, limbal stem cell deficiency (LSCD). Corneal diseases are the second leading cause of treatable blindness in the world and over 3.2 million people worldwide are bilateral blind from corneal diseases. LSCD has been recognized as a major cause, either primary or secondary, of significant visual loss and blindness in many common corneal disorders, such as chemical/thermal burn, keratopathy related to contact lens wear, and severe infection and inflammation. Due to visual impairment, LSCD patients lose the ability to drive, read, and watch TV. In addition, they would experience recurrent corneal erosion that causes severe pain and sensitivity to light. Frequent break down of the corneal surface increases the risk of infection that requires frequent medical interventions. All of these can also exert psychological impact to the patients and their family members. Therefore, LSCD imposes significant social and economical impact on our society.

California is the most populated state in the US. There are more than 36 million people in the State of California and the population will increase to 46 million in 2030. Accordingly, the number of residents with limbal stem cell deficiency is likely disproportionately elevated due to the environmental risk factors. Thus, this disease affects a large population of patients in the state of California. A new treatment to restore vision would represent an important benefit to the people of California.

Further, the project would train new stem-cell researchers and advance innovative technology in stem cell therapy. This technology has application to other stem-cell related diseases. When this project enters the clinical phase, it will bring together new physicians and scientists and attract funding by the federal government. In addition, it will undoubtedly attract biotechnology investment in California. The stem-cell based transplantation to treat a stem-cell related disease like limbal stem cell deficiency is well-aligned with the broad mission of CIRM and the objectives of the Early Translational Research Award program.

Progress Report: 
  • The proposed study is a continuation of our Early Translational Award project (Development candidate feasibility award), which aimed to develop a xenobiotic-free culture method to expand limbal stem cells (LSCs) for transplantation. We have accomplished this goal during the previous funding period. The goal of the proposed study in this bridging funding period is to further optimize the culture condition by achieving the following two aims: 1) To optimize the culture substrate in the xenobiotic-free and feeder-free culture system; 2)To optimize the culture media of the xenobiotic-free and feeder-free culture system.
  • We have completed all proposed experiments and met the milestones. Methods to improve the consistency of culture substrates have been achieved and a base culture medium has been selected from three tested base media for the expansion of LSCs. The successful optimization of our LSC culture protocol allows us to proceed with the next stage of pre-IND studies.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05739
Investigator: 
Type: 
PI
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.
  • Over the past year our laboratory has made significant progress to advance our therapy for retinitis pigmentosa (RP). We are pleased to have finally reached the stage that our human retinal progenitor stem cells will soon be tested in the clinic. We are now at the midway point in our CIRM Disease Team Therapy Development Award and our progress remains on schedule. Thus far, our manufactured cells have undergone the full array of tests in animal models to ensure that they meet all safety requirements and that they are therapeutically potent. Results have been positive, showing that allogeneic retinal progenitor cells survival transplantation to the back of the eye with no immunosuppressive agents required (except when testing across species). Additionally, we have obtained evidence in animal models of graft-associated benefits, both at the anatomical and functional levels. All of these data have been compiled, critically reviewed, and submitted to the FDA to seek approval for early stage clinical trials, thereby achieving all Year 2 Milestones for the project. As part of the approval process to commence trials, we have demonstrated the quality and consistency of the cells to be administered to patients. Each batch of manufactured cells has been shown to be free of microbial contamination and chromosomal defects and has also shown to be stable over time, ensuring suitability for use. The primary purpose of the proposed clinical trial will be to test the safety of a single intravitreal injection of human retinal progenitor cells (jCell) in patients with advanced RP. The therapy has been designed to preserve vision by intervening in the disease at a time when host photoreceptors can be protected and potentially reactivated. As a secondary outcome measure, the trial will also measure the effect of our treatment on ocular function. There will be two different dose levels of cells assessed in each of two groups of patients.
Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06601
Investigator: 
Name: 
Type: 
PI
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.

Progress Report: 
  • We are conducting a research study to find out more about the inheritance of eye diseases such as age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), proliferative diabetic retinopathy (PDR), and diabetes without retinopathy. To identify mechanisms of disease and targets for treatment, it would be helpful to study authentic retinal cells in the laboratory derived from diseased subjects as well as matched controls. This has recently become feasible due to advances in reprogramming cells into stem cells and then growing (differentiating) them into the neuronal cells. These derived cells from the biorepository will be made available for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex eye diseases.
Funding Type: 
Late Stage Preclinical Projects
Grant Number: 
LSP1-08235
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 954 514
Disease Focus: 
Vision Loss
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
Statement of Benefit to California: 

Firstly, the project itself will employ new administrative, managerial, medical and scientific personnel in California. Secondly, the development of this stem cell based drug in California will ensure that the state retains its lead in the commercialization of stem cell technologies. Finally, if successful, this treatment would provide a substantial improvement to the vision of the 15,000 Californians with progressive blindness and other forms of progressive blindness including AMD.

Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07800
Investigator: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$1 380 557
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Cell replacement therapies (CRTs) have considerable promise for addressing unmet medical needs, including incurable neurodegerative diseases. However, several bottlenecks hinder CRTs, especially the needs for improved cell manufacturing processes and enhanced cell survival and integration after implantation. Engineering synthetic biomaterials that present biological signals to support cell expansion, differentiation, survival, and/or integration may help overcome these bottlenecks. Our prior work has successfully generated synthetic biomaterial platforms for the long-term expansion of human pluripotent stem cells (hPSCs) at large scale, efficient differentiation of hPSCs into dopaminergic progenitors and neurons for treating Parkinson’s Disease, and modulation of stem cell function to promote neuronal differentiation within the brain. We now propose to advance this work and engineer two synthetic biomaterial platforms to treat neurodegenerative disease, in particular Parkinson’s Disease and Retinitis Pigmentosa. Specifically, our central goals are to further engineer biomaterial systems for scalable hPSC differentiation into dopaminergic and photoreceptor neurons, and to engineer a second biomaterial system as a biocompatible delivery vehicle to enhance the survival and engraftment of dopaminergic and photoreceptor neurons in disease models. The resulting modular, tunable platforms will have broad implications for other cell replacement therapies to treat human disease.

Statement of Benefit to California: 

This proposal addresses critical translational bottlenecks to stem cell therapies that are identified in the RFA, including the development of fully defined, xenobiotic free cell manufacturing systems and the development of clinically relevant technologies to enhance the survival and integration of human stem cell therapies. The proposed platform technologies for expanding and differentiating pluripotent stem cells in a scaleable, reproducible, safe, and economical manner will initially be developed for treating two major neurodegenerative disorders - Parkinson’s Disease and Retinitis Pigmentosa - that affect the well-being of hundreds of thousands of Californians and Americans. In addition, the biomaterial platforms are designed to be modular, such that they can be re-tuned towards other target cells to even more broadly enable cell replacement therapies and enhance our healthcare. This work will thus strongly enhance the scientific, technological, and economic development of stem cell therapeutics in California.

Furthermore, the principal investigator has a strong record of translating basic science and engineering towards clinical development within industry, particularly within California. Finally, this collaborative project will focus research groups with many students on an important interdisciplinary project at the interface of science and engineering, thereby training future employees and contributing to the technological and economic development of California.

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06648
Investigator: 
Type: 
PI
Type: 
Co-PI
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.

Progress Report: 
  • There is currently no effective treatment to restore or improve vision for patients suffering from blinding diseases such as dry, age-related macular degeneration and retinitis pigmentosa. Alleviation of these diseases requires both new photoreceptors and retinal pigment epithelium (RPE). However, a unique method to transplant fetal retinal progenitor sheets together with its supporting retinal pigment epithelium has been shown to improve vision in animal models of retinal degeneration and in patients suffering these diseases. The goal of our research is to improve current procedures to the stage in which they can be used routinely to alleviate these causes of blindness in people.
  • We are differentiating human embryonic stem cells (hESCs) into sheets of retinal progenitor tissue that contain photoreceptor progenitors and RPE cells. We anticipate that the successful completion of our research will create an unlimited supply of donor tissue that can be transplanted into the eyes of blind people. Recently, several laboratories have shown that hESCs and induced pluripotent stem cells (iPSCs) can “self-assemble” into early stages of eye development and develop into laminated structures resembling the normal retina. The hypothesis of this project is that hESCs can be consistently differentiated into sheets of retinal tissue, which can restore visual responses in an immunodeficient rat model of retinal degeneration that does not reject human cells. In the third year of our research program, we will standardize methods to increase the production of these sheets in a way that complies with good manufacturing practice. This project will ultimately help to restore vision in patients suffering from retinal diseases.
  • In year 1 of this 3-year grant, the optimal procedure for differentiation of hESCs into laminated 3D-retina has been developed and tested. This method is based on selection of tissues developing into retinal progenitor cells, and culturing them in suspension (non-attached). We have shown by quantitative PCR and by immunohistochemistry that these tissues express retina-specific genes in a time sequence comparable to human retinal development. We have built up the capabilities for testing hESC-derived 3D retina in vivo. We have set up a colony of immunodeficient retinal degenerate (RD) rats (which do not require immunosuppression), and refined the transplantation, imaging and testing techniques. To hone our skills, we have started with transplants of rat and human fetal retinal tissue. We will start with transplantation of hESC-derived 3D retina in March 2015 and continue with testing the tissue through the remainder of the grant. The development of the transplants in vivo is monitored by high-resolution optical coherence tomography which can image retinal layers. Transplanted RD rats are tested by various methods (optokinetic tracking for visual acuity, electroretinograms and recording of visual responses from the superior colliculs, a visual brain center) to demonstrate the transplant effect on vision. In the first year of the grant, we have shown that these methods can demonstrate the improvement of vision by fetal-derived transplants
  • This work will be presented in several posters at this year’s ARVO meeting; several manuscripts are in preparation. The laboratory has attracted many students who are interested to learn about retinal development and vision restoration.
Funding Type: 
Research Leadership
Grant Number: 
LA1-02086
Investigator: 
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.

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