Prevention of posterior capsule opacification by the induction of therapeutic apoptosis of residual lens cells.
Posterior capsule opacification (PCO) is a common complication of cataract surgery. Using adenovirus(Ad)-mediated gene transfer, we overexpressed the proapoptotic molecules p53, procaspase 3, Bax, and TRAIL to induce therapeutic programmed cell death of residual lens cells to prevent PCO. Overexpressed TRAIL did not induce apoptosis in cultured rabbit lens cells or in human lens cells. Overexpressed p53 induced apoptosis of lens cells in vitro and ex vivo, but was unable to prevent PCO in vivo. Overexpressed procaspase 3 was associated with engagement of many components of the apoptotic pathway, including cleavage of intracellular caspase targets such as PARP and inter-nucleosome DNA fragmentation. Even when only slightly overexpressed, Bax caused apoptosis of transduced rabbit and human lens cells by engaging the mitochondrial pathway, including catalytic activation of the caspases. A single in vivo injection of Ad vectors expressing either Bax or procaspase 3 into the capsular bag at the end of phacoemulsification prevented PCO in rabbits. These experiments show that Ad-mediated Bax or procaspase 3 overexpression is capable of inducing therapeutic programmed cell death in vitro and in vivo in residual lens cells and preventing PCO in a rabbit model of PCO. Manipulation of proapoptotic molecule expression could be a novel gene therapy approach for prevention of PCO.
Malecaze
F
F
INSERM U563, Department Ophtalmologie et Pathologie des épithéliums, Hôpital Purpan, Toulouse, France. malecaze.fr@chu-toulouse.fr
Decha
A
A
Serre
B
B
Penary
M
M
Duboue
M
M
Berg
D
D
Levade
T
T
Lubsen
N H
NH
Kremer
E J
EJ
Couderc
B
B
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology; D019573:Epithelium, Corneal / Q000473:pathology; D005786:Gene Expression Regulation; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007903:Lens Capsule, Crystalline / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D018918:Phacoemulsification; D011183:Postoperative Complications / Q000473:pathology / Q000628:therapy*; D011817:Rabbits; D053221:TNF-Related Apoptosis-Inducing Ligand; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases