Development of Cellular Therapies for Retinal Disease

Funding Type: 
Research Leadership
Grant Number: 
Award Value: 
Disease Focus: 
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
iPS Cell
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.

Scaring and uncontrolled neovascularization are components of several blinding disorders]. One of those diseases is age-related macular degeneration (AMD), a progressive disorder affecting the central region of the retina. It is the leading cause of blindness for Caucasians in the United States, with 6.5 % of the total population aged 40 years and older having symptoms of AMD to some degree. Dysfunction of the retinal support cells of the retinal pigmented epithelium (RPE) is generally considered to be central to the etiology of AMD. The RPE performs a number of unique functions essential for the sight and the maintenance of a healthy eye.
The first clinically recognized signs of AMD are the accumulation of macular extracellular deposits, named drusen, which stop the normal function of the eye. During these initial stages of the disease, classified as early AMD], there is minimal perceptible loss of vision. Prominent loss of vision is only associated with late or advanced AMD, which is characterized by deterioration and death of the RPE.
The transition from early to advanced AMD has features consistent with the onset of a wound response resulting from an underlying degenerative disease and chronic inflammation. We report findings directed at furthering our understanding of the molecular basis of RPE wound response, its likely impact on RPE function, and possible role in AMD. Using a cell culture model system coupled with a systems biology, we identify changes in expression in a number of genes encoding that play a role in wound response. Finally, we investigate the possible role for wound responses in AMD by comparing the changes in gene expression in this cell culture model to previously reported AMD-associated gene expression changes.

In this fourth year, we have turned our attention on ageing and susceptibility to disease. As defined by the name, age-related macular degeneration occurs in old rather than the young. As such, we need to know why the eye and in particular those cells that support healthy vision deteriorate over time. Over the past year, we have identified that the cellular fingerprint of those eye cells begins to decline. This results in a less able functional cell. Our aim is to reduce this decline by slowing or inhibiting cellular changes seen in aging.
Second, we have been involved with the London Project to Cure Blindness in which two patients were implanted with new support cells which were made from stem cells and delivered on an artificial substrate. These patients will be followed over the next 6-12months for any visual recovery.