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Gene Therapy

Paul Kaufman

1. Gene therapy need not be related to disease-causing genes. Rather, it is changing what a cell does in a way that is therapeutically useful. It is analogous to drug therapy; for example, we suppress aqueous formation, even though aqueous humor formation in glaucoma is entirely normal.
2. Causing a cell to over- or under express a protein in a glaucoma-therapeutically useful manner.
   1. RGC or surrounding cells to make a protein with anti-apoptotic actions.
   2. TM cells to make a protein that inhibits cellular contractility and thereby relaxes the TM and weakens cell adhesions in the TM, with a consequent increase in outflow facility (as is seen following topical administration of small molecules that affect these biochemical pathways in a similar manner).
   3. Ciliary muscle cells to overexpress PGF synthase or an MMP to increase uveoscleral outflow (rather than giving a PG analog topically every day).
   4. Ciliary NPE cells to overexpress an enzyme that slows the production of CA or alters an ion channel, reducing AHF.
3. Method: Viral vectors _ nature's gene delivery system. Other methods for gene transfer exist, but this is the one most under study.
4. Advantages:
   1. Patient is not the delivery system _ better compliance.
   2. Long term expression _ no need for daily administration.
   3. Possible targeting of specific cell types with a cell type-specific promoter.
5. Disadvantages:
   1. Other cells might be affected.
   2. Inflammation due to immune response.
   3. Viral toxicity.
   4. Need longer expression duration than currently achieving.
6. Where are we?
   1. Can transfer reporter genes to human TM and CM cells in culture.
   2. Can transfer reporter genes to ciliary NPE and TM in live monkeys.
   3. Can transfer cell contractility inhibiting genes to TM in organ culture monkey eyes, and demonstrate expression of protein and increased outflow facility.
7. Next steps:
   1. Better vectors! Less toxicity and immunogeneicity.
   2. Longer duration of expression.
   3. Site-specific gene transfer.
   4. Inducible promoters or other means of turning the gene off if needed.