Human Embryonic Stem Cell Therapy for Retinal Degeneration

Funding Type: 
SEED Grant
Grant Number: 
RS1-00420
ICOC Funds Committed: 
$0
Disease Focus: 
Blood Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Approximately 1.1 million Americans are legally blind. A form of retinal degeneration called age-related macular degeneration (or AMD) is the most common form of blindness in older Americans, affecting almost 1 in 3 individuals older than age 75. The macula is the critical portion of the retina that is required for central vision and for seeing color and fine detail. The retina is the tissue at the back of the eye that senses light and conducts visual signals to the brain. Other forms of retinal degeneration, such as retinitis pigmentosa, may affect other areas of the retina or even the entire retina. These conditions are inherited and affect individuals in their earlier years, limiting their lives at a time when they could be most productive. No cures are currently available for patients with any of these blinding eye diseases. The long-term goal of our proposed experiments is to develop therapies for these patients using human embryonic stem cells (hESC). These cells have the unusual ability to develop into any cell type in the body, a characteristic that suggests they may have the potential to restore lost or damaged tissue anywhere in the body. Researchers have previously shown that hESC can be cultivated into cells with the characteristics of developing retinal cells (retinal progenitor cells). However, these cells have not yet been tested for their ability to treat retinal degeneration. We believe that properly modified retinal progenitor cells derived from hESC could be used to preserve or even replace damaged retinal tissue. Our laboratory also does research on a tumor of the retina, retinoblastoma, which arises from retinal progenitor cells. Current evidence indicates that if these cells can be modified to curb their growth, they may also serve as useful source of tissue for restorative therapy in patients with retinal degenerations. We propose to investigate these potential cell-based therapies by: 1. Creating hESC-derived retinal progenitor cells and genetically engineered retinoblastoma cells with the potential to preserve or replace damaged retina. 2. Transplanting these cells into special strains of rats with partial retinal degeneration. Analysis of retinal function in these rats will determine whether hESC can slow or prevent further retinal deterioration. 3. Transplanting these cells into rats and mice with complete retinal degeneration to determine whether these cells can regenerate functional retina and restore vision. We believe this work has low likelihood to be funded by the federal government because of the current funding climate and the fact that only limited work in this research area has been federally funded. Nonetheless, we believe the eye is an ideal organ system for testing the therapeutic potential of hESC because it is amenable to precise functional and electrophysiologic assessment of treatment response. In addition, the eye is an immune privileged site that is less likely to reject implanted tissue.
Statement of Benefit to California: 
The economic costs associated with visual disability are enormous. The National Eye Institute estimates that the annual cost of visual disorders and disability in the U.S. was $67.6 billion in 2003 (http://www.nei.nih.gov/eyedata/hu_estimates.asp). These costs include direct expenses such as visits to doctors, surgery, ophthalmic drugs, hospital care and optical devices in addition to indirect costs such as days lost from work. Assuming the cost of visual disability in California is proportional to its percentage of the U.S. population, the economic burden of visual disability in California exceeds $8 billion per year. This estimate does not include the additional costs of educating children with visual impairments. According to a report commissioned by the California Department of Education, over 5,046 special education students in the public school system required vision services. The average cost of special education services for students with visual impairment was $21,745, resulting in a total cost to the state of nearly $110 million in that year. (Study of the Incidence Adjustment in the Special Education Funding Model, Exhibits 2-35 and 4-2, http://www.cde.ca.gov/fg/fr/se). The development of more effective treatments to reduce visual disability would therefore have a tremendous positive economic impact on the state as a whole. Such innovations would also greatly improve the quality of life of Californians suffering from diseases of the eye. The most frequent cause of blindness in the United States is age-related macular degeneration (AMD), a disease that affects 30% of Americans over the age of 75 (Klein R et al, Ophthalmology 99:933-943, 1992,). The incidence of this disease ranges worldwide up to 41.6% in older populations (Hirvela H et al, Ophthalmology 103:871-877, 1996). The incidence of age-related macular degeneration in California will continue to rise as the baby boom generation ages. Retinal degenerative diseases like AMD are characterized by loss of photoreceptors, the light-sensing cells of the eye. In patients with AMD, photoreceptor loss results in loss of central visual acuity. When central vision is lost, patients also lose their ability to read, to drive, to work, and to interact with the visual world. Other retinal degenerative diseases, such as retinitis pigmentosa, can be inherited and affect individuals in their earlier years, limiting their lives at a time when they could be most productive. No cures are currently available for patients with these blinding eye diseases. The long-term goal of our proposed experiments is to develop human embryonic stem cell (hESC) based therapies which can slow photoreceptor loss in patients in early- to mid-stage retinal degeneration, and possibly even replace lost photoreceptors and restore vision in patients blinded by end-stage disease. We hope that this work will lead to better understanding of retinal degeneration and potentially a cure for these debilitating diseases.
Progress Report: 
  • Our goal has been to improve the microenvironment where human embryonic stem cells (hESC) differentiate in order to generate functional hematopoietic stem/progenitor cells (HS/PC) in culture, with the ultimate goal to use these HS/PCs for the treatment of leukemias and other blood diseases. We have tested various human and mouse stroma lines for their ability to support expansion of multipotential human HS/PCs as well as hematopoietic specification from hESCs. So far mouse mesenchymal stem cells (MSC) have proven to provide the best supportive ability for human hematopoiesis. By combining embryoid body differentiation and co-culture on mouse MSC stroma, we have succesfully generated HS/PCs that phenotypically resemble bona fide human HSCs (CD34+CD38-CD90+CD45+). However, so far their differentiation ability has been biased toward myeloerythroid cells, with poor ability to generate B-cells in culture. Based on microarray data that we obtained from a related project supported by the CIRM New Faculty Award, we have identified molecular programs that are defective in hES derived HS/PCs. Future efforts will be directed in modifying the culture microenvironment as well as the cell intrinsic regulatory machinery in hES derived HS/PCs in order to improve their differentiation and self-renewal potential.
  • Our goal has been to improve the microenvironment where human embryonic stem cells (hESC) differentiate in order to generate functional hematopoietic stem/progenitor cells (HS/PC) in culture, with the ultimate goal to use these HS/PCs for the treatment of leukemias and other blood diseases. We have optimized a two step differentiation protocol that combines embryoid body differentiation and subsequent stroma co-culture to generate HS/PCs that exhibit the same phenotype as HSCs obtained from human hematopoietic tissues (CD34+CD38-CD90+CD45+). However, our findings indicate that the hESC derived HS/PCs have restricted developmental potential as compared to fetal liver or cord blood derived HS/PCs, and they senesce prematurely in culture, and are unable to generate B-cells . Our functional and molecular studies suggest that hES-derived HS/PCs resemble closely lineage-restricted progenitors found early in development in human hematopoietic tissues. Our recent studies have focused on exploring the possibility that another precursor that develops in the embryoid bodies could have lymphoid potential when placed in an appropriate microenvironment. Our preliminary data suggests that development of T-lymphocytes from hESCs in vitro may be feasible. Our future work will continue to focus on generating fully functional HSCs by improving the in vitro microenvironment where HS/PCs develop, and/or programming HSC transcriptional program using inducible lentiviral vectors.

© 2013 California Institute for Regenerative Medicine