Gene therapy using p21WAF-1/Cip-1 to modulate wound healing after glaucoma trabeculectomy surgery in a primate model of ocular hypertension.
Glaucoma is a common eye disease associated with elevated intraocular pressure (IOP). Lowering IOP is the only acceptable therapy for glaucoma and slows progression of the disease. Filtration surgery, which introduces a guarded ostomy through the sclera into the anterior chamber of the eye to allow the escape of aqueous humor, is the most reliable method for effective IOP lowering. Success of this surgery is limited by scarring of the ostomy, so this procedure is often accompanied by the use of antimetabolites, such as mitomycin C (MMC), to block the wound healing response. Although effective in preventing scarring, antimetabolites also yield unwanted side effects, such as hypotony and tissue degeneration due to cellular destruction. This study presents an alternative to antimetabolites by using gene therapy to introduce the human gene for p21(WAF-1/cip-1) (p21) to cause cell cycle arrest of surrounding cells rather than their destruction. In this procedure, p21 was delivered using a recombinant adenovirus to ocular hypertensive monkey eyes. These eyes then underwent filtration surgery. Results show that eyes treated with p21 exhibited open surgical ostomies by both functional and histological criteria, and did not display any side effects seen in control animals that were treated with MMC.
Glaucoma Research Group, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, 53706, USA.
G
G
Heatley
J
J
Kiland
B
B
Faha
J
J
Seeman
C L
CL
Schlamp
D G
DG
Dawson
J
J
Gleiser
D
D
Maneval
P L
PL
Kaufman
R W
RW
Nickells
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005901:Glaucoma / Q000601:surgery* / Q000628:therapy; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D016685:Mitomycin / Q000627:therapeutic use; D023421:Models, Animal; D011897:Random Allocation; D014130:Trabeculectomy; D014161:Transduction, Genetic / Q000379:methods; D014945:Wound Healing
D000963:Antimetabolites; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016685:Mitomycin