(Applicant?s Abstract) The long-term goal of this research program is to deliver a gene product (i.e. gene therapy) which will increase extracellular matrix turnover specifically in the trabecular meshwork (TM) to lower intraocular pressure for the treatment of glaucoma. Two major obstacles to gene therapy in the trabecular meshwork are the lack of a tissue-specific delivery system and the lack of an effective gene which would lower IOP if successfully transfected. The general hypotheses are: (1) that a retroviral vector combined with laser-induced mitosis will deliver genetic material specifically to the trabecular meshwork and (2) that inacrophage migratory inhibitory (MIF) will cause an increase in extracellular matrix breakdown. These hypotheses will be tested by determining if the retroviral vector will transfer a reporter gene to dividing human and rabbit trabecular meshwork cells in culture. These studies will then be expanded to test the selectivity of the retroviral vector combined with laser-induced mitosis (RVCLIM) system in human and rabbit organ explant cultures and in rabbit eyes, in vivo. Additional studies will investigate MIF?s ability to upregulate the expression and activity of matrix metalloproteinases in cultured trabecular meshwork cells. If these experiments are successful, the RVLIM gene . delivery system could be used therapeutically and as a tool to study the biology of the TM. These studies would set the foundation for future evaluations of the function of MIF in the TM and MIF?s potential as a candidate for gene therapy for the treatment of glaucoma.
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