Molecular Mechanisms of Glaucoma and Gene Therapy
Principal Investigator: Terete Borras, Ph.D.
Ocular pressure is maintained inside the eye by the continuous flow of the aqueous humor through the trabecular meshwork tissue (TM) into the Schlemm's canal. The cells of the TM play a key role in maintaining the physiological resistance that keeps the ocular globe inflated. A TM malfunction results in an abnormal resistance and in turn, in an elevated intraocular pressure (IOP). The high pressure, if uncontrolled, would result in damage to the optic nerve and irreversible blindness. This disease, Glaucoma, is the second most important cause of non-remedial blindness in the USA.
The overall long-term goal of our research is to understand the mechanisms of aqueous humor outflow resistance at the molecular level by the use of gene transfer technology. By changing the concentration of key proteins and enzymes inside the cells we are seeking to find and deliver genes to the trabecular meshwork that could infuence aqueous humor outflow facility.
We are currently following two lines of investigation:
- Identification of genes involved in the regulation of glaucomatous insults (Gene Search).
- Develop efficient gene delivery to eye tissues involved in causing glaucoma (Gene Therapy).
The Gene Search program involves the identification of genes that are up or down regulated by elevated intraocular pressure. The strategy for the development of this project combines the use of perfused organ cultures from post-mortem donor human eyes, differential expression, and GENE CHIP Array technology. Using these methods, Dr. Borras has identified a panel of previously undescribed genes in the trabecular meshwork.
For the Gene Therapy program, Dr. Borras's group is attempting to modify intraocular pressure by delivering therapeutic genes and proteins to the trabecular meshwork. Her current efforts are focused on the use of recombinant adenoviral vectors carrying reporter and selected genes as well as those genetically linked to glaucoma. One single injection of recombinant adenoviruses transduced the reporter protein to all cell layers of the trabecular meshwork for a period of up to four weeks. The efficiency and toxicity of these gene vectors is evaluated in human organ cultures and in living animals.
We believe identification of relevant genes together with the development of gene delivery methods would provide us with the information and tools necessary to be able to treat Glaucoma in the future with Gene Therapy.