Thapsigargin-coated intraocular lenses inhibit human lens cell growth

Abstract

Cataract is responsible for rendering several million people blind throughout the world and is also by far the most common cause of low visual acuity. Although cataract surgery is common, routine and effective, posterior capsule opacification (PCO) occurs in 30-50% of patients following modern cataract surgery. This condition arises from stimulated cell growth within the capsular bag after surgery. The resulting decline in visual acuity requires expensive laser treatment, and PCO therefore prevents modern cataract surgery from being carried out routinely in underdeveloped countries. The present study, using a human lens capsular bag culture system, has confirmed that cells from a wide age range of donors proliferate in the absence of added serum protein and explains why PCO is such a common problem even in aged patients. This study also provides one possible solution for PCO by using polymethylmethacrylate (PMMA) implanted intraocular lenses as a drug delivery system. PMMA lenses coated with thapsigargin, a hydrophobic inhibitor of endoplasmic reticulum (ER) (Ca2+)-ATPase, greatly reduced cell growth in the capsular bag at relatively low coating concentrations (200 nM) but, more significantly, induced total cell death of the residual anterior epithelial cells at higher concentrations (>2 microM).

MMP2 Activity is Critical for TGFβ2-Induced Matrix Contraction—Implications for Fibrosis

“…This drug delivery method has been used in the past for a number of molecules. 57,58 Interestingly, the effect of the MMP2 inhibitors GM6001, MMP2/9 inhibitor I, and MMP2/9 inhibitor II on ocular cell migration and viability were tested, along with longterm release rates from silicon-coated disks (a material commonly used to make IOLs). 59 Silicon disks coated with high concentrations of MMP2/9 inhibitor II reduced migration of FHL-124 cells by > 42%.…”

Irrigation with thapsigargin and various concentrations of 5-fluorouracil in a sealed-capsule irrigation device in young rabbit eyes to prevent after-cataract

“…14,15 Coating polymethylmethacrylate lenses with thapsigargin effectively prevented LEC proliferation in an in vitro study of human capsular bags.…”

“…In cell culture, thapsigargin and 5-FU 25 mg/ml effectively killed the cells. The explanation for why thapsigargin is more effective in human LECs than in rabbit LECs is unknown; however, Duncan et al 14 proposed that the rabbit model often uses young animals whereas the human donor eyes most often are older. The rabbit cells are, therefore, more sensitive to stress than the human cells.…”

“…We also evaluated thapsigargin, a hydrophobic inhibitor of endoplasmic reticulum (Ca 2 þ )-ATPase, which has proved effective in in vitro studies of human lens capsules. 14,15 This study was conducted to compare balanced salt solution (BSS), 5-FU 50 mg/ml, 5-FU 25 mg/ml, and thapsigargin in a sealed-capsule irrigation device to determine the substance that is most effective in preventing after-cataract formation and postoperative inflammation.…”

Electrical inhibition of lens epithelial cell proliferation: an additional factor in secondary cataract?

“…PCO severely compromises vision in many patients having cataract surgery, but there is as yet no completely effective method for preventing it (10). It has been shown that the use of an intraocular lens coated with thapsigargin, which kills LECs, prevents PCO ex vivo (11). Proliferation and directed migration of LECs are key events in PCO.…”