Generation of transplantable human limbal epithelial cells from induced pluripotent stem cells for limbal stem cell deficiency

Funding Type: 
Early Translational IV
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Corneal blindness affects millions of people. One of its causes is deficiency of corneal epithelial stem cells (LESC) renewing corneal outer lining. LESC deficiency (LSCD) may be due to genetic defects, burns, infections, and inflammation. It causes corneal scarring, blood vessel growth and outgrowth of conjunctiva, all of which lead to vision loss. Keratolimbal grafts allowed in U.S. have 30% 5-year survival. Cultured LESC are transplanted in other countries, with 70% 5-year success rate, but allograft survival is low. We propose to fight LSCD using induced pluripotent stem cells (iPSC). Unlike LESC, iPSC may be banked and standardized. Making iPSC from corneas, rather than from distantly related fibroblasts, and differentiating them back to corneal cells may create a reliable cell source for transplantation. If LSCD affects both eyes, one has to use donor cells, leading to lifelong immunosuppressant use. To address this issue we will use for the first time closely related conjunctival cells to make iPSC and then corneal cells. Conjunctiva cannot substitute for the damaged cornea, but its stem cells can be pushed to become cornea-like cells in specific conditions. This would allow treating LSCD with patient’s own cells. Our innovative study will provide a proof of concept for the target product by developing iPSC-derived cells for future transplantation in LSCD. The standardized product will be amenable to safety and toxicity tests, and would lead to animal and human trials.

Statement of Benefit to California: 

Eye burns, chronic inflammation, and infections damage corneolimbal stem cells (LESC) often causing limbal stem cell deficiency (LSCD), which compromises vision. Burns represent 7-10% of eye injuries. About 15-20% of burns to the face involve at least one eye and are a frequent occupational hazard. An estimated 20% of population suffers from an eye trauma in their lifetime. The rate of eye injuries is estimated to be about 120,000 annually for California with 38 million residents. About 24,000 people in California have aniridia, a genetic defect usually resulting in untreatable LSCD. Thus, LSCD is a serious and hard to treat eye condition. In the U.S., only limbal grafts are allowed, which restricts the number of cases where this treatment may bring long-term benefit to the patient, and cannot be used if both eyes are damaged. To address this unmet and urgent clinical need, we propose to use induced pluripotent stem cell (iPSC) technology to produce a bankable and renewable source of LESC that could be used for transplantation in the affected people including Californians. Our goal is to produce such cells for the first time from the patient’s own tissue close in properties to the cornea, thus alleviating the need for lifelong use of immunosuppressive drugs. If successful, this exciting new approach would pave the way for human trials and clinical use of patient’s cells for transplantation in LSCD, a vision-threatening eye condition affecting many thousands of Californians.