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Adenovirus-Mediated Gene Therapy Using Human p21WAF-1/Cip-1 to Prevent Wound Healing in a Rabbit Model of Glaucoma Filtration Surgery
Todd W. Perkins, MD;
Barbara Faha, PhD;
Ming Ni, MD;
Julie A. Kiland;
Gretchen L. Poulsen;
Doug Antelman, PhD;
Isabella Atencio, PhD;
Jeremy Shinoda;
Dinesh Sinha, PhD;
Lyndia Brumback, MS;
Daniel Maneval, PhD;
Paul L. Kaufman, MD;
Robert W. Nickells, PhD
Arch Ophthalmol. 2002;120:941-949.
Objective To determine if adenovirus-mediated p21WAF-1/Cip-1 (p21)
gene therapy can prevent fibroproliferation and wound healing in a rabbit
model of glaucoma filtration surgery.
Methods In vitro studies were performed using rabbit Tenon fibroblasts harvested
from fresh tissue. In vivo studies were conducted in New Zealand white rabbits.
A full-thickness sclerotomy was performed under a limbal-based conjunctival
flap. Reagents tested included a replication-deficient recombinant adenovirus
containing the human p21 gene (rAd.p21); the nonspecific marker gene for green
fluorescent protein or  -galactosidase; mitomycin, 0.5 mg/mL; and balanced
saline solution. Each treatment was applied episclerally for 5 minutes before
the sclerotomy using a soaked cellulose sponge placed under the surgically
created conjunctival flap. Independent experiments were conducted to (1) monitor
changes in intraocular pressure during a 30-day period after treatment and
examine surgical site histological features, (2) examine changes in bleb morphologic
features over 30 days, (3) determine outflow facility 14 days after treatment,
and (4) examine the localization and persistence of rAd.p21 expression between
3 and 60 days after treatment.
Results Treatment of Tenon fibroblasts with rAd.p21 resulted in a dose-dependent
inhibition of DNA synthesis and cell growth in vitro. In vivo, rAd.p21 inhibited
wound healing and fibroproliferation after filtration surgery, comparably
to mitomycin. Mitomycin caused notable thinning of the bleb wall. In addition,
2 of the 5 mitomycin-treated eyes exhibited an abscess with hypopyon and hyalitis
30 days after surgery, which was not observed in any of the rAd.p21-treated
eyes. None of the treatments resulted in a significantly sustained decrease
in intraocular pressure during the 30-day period, although mitomycin treatment
resulted in a significant (P = .02) increase in outflow
facility 2 weeks after surgery in separate animals. Mitomycin- and rAd.p21-treated
eyes had functioning blebs at the end of the experiment based on slitlamp
examination.
Conclusions Mitomycin and rAd.p21 were effective in preventing fibroproliferation
and wound healing in a rabbit model of glaucoma surgery. Mitomycin treatment
increased outflow facility in normal-pressure eyes.
Clinical Relevance Gene therapy with rAd.p21 may provide an effective antiproliferative
for glaucoma filtration surgery, without the complications associated with
mitomycin.
From the Departments of Ophthalmology and Visual Sciences (Drs Perkins,
Kaufman, and Nickells and Mss Kiland and Poulsen) and Biostatistics and Medical
Informatics (Ms Brumback), University of Wisconsin, Madison; Canji, Inc, San
Diego, Calif (Drs Faha, Ni, Antelman, Atencio, and Maneval and Mr Shinoda);
and Schering Plough Research Institute, Lafayette, NJ (Dr Sinha). Drs Kaufman
and Nickells have worked as consultants to Canji, Inc.
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