Mesenchymal Stem Cell Therapy for Combat Related Ocular Surface Injuries (funded by Department of Defense)

This study aims to develop a novel treatment for Service Members suffering from non-penetrating injuries to the eye surface. The specific injuries range from the common corneal abrasion, i.e., a scratch, to the more severe thermal and chemical burns. The latter can result from explosions, fires, or from exposure to chemical agents, e.g., mustard gas.

We plan to develop a new treatment that will (1) accelerate healing and promote a faster return to a Service Member's normal level of functioning, and (2) prevent the development of such secondary problems as scarring and loss of vision that often follow the initial burn injuries.

The development target, an eye drop treatment, consists primarily of a stem cell "broth." The principal agent producing this broth is a type of stem cell, known as a mesenchymal stem cell, found in many tissues in the body. Currently, a number of ongoing research studies are exploring and showing their healing effects. For instance, these stem cells are being injected directly into the heart of heart attack patients to see if it will help repair the heart muscle. Likewise, these stem cells have been shown to promote healing of the surface of the eye after injuries.

In a slight departure from other stem cell studies, instead of using the actual cells on the eye, we propose using a "broth" that contains the factors that are produced by these cells. In fact, we have already found that by growing stem cells in a solution in the laboratory, the solution itself (the broth without the actual cells) has great healing effects for eye injuries in mice.

Therefore, we are planning to study and develop the stem cell broth as a treatment for eye injuries in patients. We are specifically planning to test several different conditions to optimize the stem cell broth and determine the best conditions for collecting the broth. We are projecting 3 years to finish our study and development. At the end of this period, we will have an eye drop, ready to be used clinically to promote healing in Service Members with combat related corneal injuries.

MECHANISMS OF CORNEAL EPITHELIAL DISEASE AND REPAIR (funded by NEI/NIH)

The corneal epithelium is one of the most sensitive and critical structures of the eye. It is affected in nearly every disease of the ocular surface, ranging from corneal abrasions and dry eyes to severe corneal melts and infections. Currently, there are very limited treatments that can specifically enhance the corneal epithelial function. In particular, there are no pharmacologic approaches to promote epithelial repair in patients with a compromised corneal epithelial barrier. The long term objective of this research application is to contribute to the development of novel and innovative treatments for patients with visually disabling ocular surface diseases by defining the mechanisms of epithelial barrier disease and repair. Our preliminary studies provide strong evidence that Notch1 plays a key role in regulating the corneal epithelial barrier repair and thus Notch1-/- mice provide a unique model for studying corneal epithelial barrier disease. To accomplish the research objectives of this application, the following two specific aims will be pursued: (1) Characterize the epithelial barrir function and the cell-cell adhesion defect using mice with conditional loss of Notch1 as a model, (2) Elucidate the inflammatory signaling pathways that are activated during epithelial injury/repair and determine their role in the development of inflammation and metaplasia using Notch1-/- mice as a model. These results will provide critical information for the development of therapies for patients with visually disabling ocular surface disorders. We will identify a number of candidate pathways and drugs for clinically enhancing the function of the corneal epithelium and suppressing corneal inflammation.

Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE: A clear cornea is essential for normal vision. The most superficial layer of the cornea, known as the epithelium, is affected in many disorders that result in severe visual impairment. This project aims to find new treatments that will enhance the function of the corneal epithelium, particularly ways to improve its integrity and protective function.

Clinical Translation of Mesenchymal Stem Cell based Therapy for the Corneal Disease in Aniridia (Funded by Vision For Tomorrow)

The goal of this research is to develop a novel treatment for patients with aniridic corneal disease. The specific disease processe targeted will be limbal stem cell deficiency that develops in aniridic patients. We plan to develop a new treatment that will prevent and potentially reverse the loss of limbal stem cells. The proposed treatment is based on mesenchymal stem cell (found in many tissues in the body). Currently, a number of ongoing research studies are investigating the healing and regenerative effects of these stem cells. We propose using the actual cells and/or their secreted therapeutic factors that are produced by these cells. We specifically plan to test different conditions to optimize the stem cells and the secreted factors and determine the optimal treatment for preventing and potentially reversing limbal stem cell deficiency in aniridia.