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BA Faha, G Heatley, J Kiland, J Seeman, D Maneval, P Kaufman, R Nickells; Antiproliferative p21WAF-1/Cip-1 Gene Therapy and Trabeculectomy Controls IOP and Reduces Optic Nerve Damage in a Primate Model of Glaucoma . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1940.
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Purpose:Failure of glaucoma surgery is due to the hyperproliferation of ocular fibroblasts (conjunctival and Tenons). Current trabeculectomy techniques include the use of anti-proliferatives such as mitomycin C (MMC) and 5-FU. However, undesirable side effects or burdensome treatment regimens have stimulated the development of alternative anti-proliferatives. We have investigated the utility of gene therapy to reduce post-trabeculectomy scarring using a recombinant adenovirus encoding the p21 protein, rAd-p21. p21 negatively regulates the cell cycle by inhibiting cyclin-dependent kinases, which are required for cell cycle progression. Methods:Elevated IOP was induced in one eye of 16 Macaca fasicularis monkeys by ablative laser trabeculoplasty. After stabilization of high IOP, a partial thickness trabeculectomy was performed in the affected eye. The animals were separated into 4 groups that received either topical application of balanced saline solution (BSS), 0.5 mg/mL MMC, rAd-p21 (∼7E10 particles) or rAd with no transgene (∼7E10 particles) as antiproliferative agents at the time of surgery. All animals were monitored with tonometry, slit lamp exams, and optic disc photography over a mean period of 260.5 days after surgery. Results:Changes in IOP were monitored relative to the IOP in the fellow un-operated eye of each monkey. All animals showed prominent blebs and a decrease in IOP to normal levels immediately following surgery. Eyes treated with MMC developed late depigmentation of the conjunctiva in the surgical region. Within 2-3 weeks post surgery, IOP returned to elevated levels in most of the BSS and rAd controls. Eyes treated with MMC showed variable effects, with only 1 eye exhibiting a sustained lowered IOP, even though all eyes had obvious blebs. All eyes treated with p21 maintained a low post-operative pressure during the course of the experiment. Blebs in these eyes were of very low volume. No significant complications were observed with any treatment. Analysis of optic nerve head photographs indicated that lowering IOP correlated with cessation of cupping. Retinal and nerve glaucomatous damage is being evaluated histologically. Conclusion:Our findings suggests that rAd-p21 could be a useful therapeutic to prevent glaucoma surgery failure. This study was supported by a grant from Canji, Inc.
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