Stem Cells for Neuroprotection of Photoreceptors in Retinitis Pigmentosa

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01444
ICOC Funds Committed: 
$0
Disease Focus: 
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 
The targeted disease is retinitis pigmentosa (RP), is a severe form of blindness that runs in families. This disease is not 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 but 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 the rods and cones can be spared in animals by transplanting particular types of stem cells, so the scientific feasibility of treating RP has already been established in principle. The therapeutic approach 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 rescuing photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at turning into 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 incurable diseases of the brain and spinal cord.
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 and central nervous system that could benefit from the type of stem cell therapy proposed in the current application. The rapid progress that could be achieved via this proposal would help legitimize the use of stem cells and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other diseases. 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 {REDACTED}, and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues.
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.

© 2013 California Institute for Regenerative Medicine