Development of stem cell-based therapies for limbal stem cell deficiency

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Project summary/Abstract: Corneal blindness is the fourth leading cause of blindness in the world. Limbal stem cell deficiency (LSCD) is a blinding eye disorder due to the dysfunction or absence of corneal epithelial stem cells or limbal stem cells (LSCs), which maintain the normal homeostasis of the transparent corneal epithelium. LSCD, which is often undiagnosed and most challenging to treat is seen in many common eye diseases. The most desired treatment is transplantation of autologous LSCs in severe/total unilateral LSCD. The efficacy of transplantation of cultivated LSCs (cLSCs) has been reported in more than 37 studies since 1997. However, the cultivation protocol and the clinical outcome measures vary from study to study. Only three studies used GMP-compliant cLSCs. In addition, the success rate has not improved over the last two decades. To improve the efficacy and safety profile of the cLSCs, clinical trials using a standardized LSC cultivation and clinical protocol are necessary. To accomplish this goal, our laboratory has established a xenobiotic-free and feeder-free LSC culture method that can consistently produce cLSCs with properties that meet the criteria for high-level clinical success. Quantifiable in vitro parameters have been developed to characterize cLSCs and a newly developed in vivo imaging technique can be used to quantify LSC function in patients. In this proposal, we will establish these quantifiable in vitro parameters as in-process quality controls for the production of cLSCs and establish in vivo parameters as clinical outcome measures to objectively assess clinical outcomes. A pilot clinical study to evaluate the safety and efficacy of cLSCs produced under GMP condition will be conducted. Implementation of these in vitro and in vivo quantifiable parameters will make it possible to establish a standardized patient- specific stem cell therapy. The knowledge learned from the proposed study will form the foundation for the development of the next generation patient-specific limbal stem cell therapy.