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| September 2002 | Inside IOVS | Volume 43/9 |
| Therapeutic Approaches to Treating Ocular Diseases |
IL-1 RA Protects Corneal Stem Cells
Residual corneal stem cells may initially survive despite limbal stem cell failure and ingrowth of conjunctiva. Moore et al. (p. 2905) show that the conjunctivalized surface, though grossly inflammation-free, harbors increased levels of pro-inflammatory cytokines and adhesion factors. This environment could result in continued damage to residual corneal stem cells. Using IL-1RA (a naturally occurring antagonist to IL-1) in the form of gene therapy, it was possible to ameliorate this inflammatory milieu. In addition, gene therapy to transplanted limbal grafts resulted in decreased inflammatory cell influx. This form of gene therapy allows treatment with single or multiple genes to attempt to sustain or increase levels of corneal epithelial stem cells.
Taurine Promotes Corneal Cell Survival
Exposing cultured human corneal epithelial cells to hypertonic challenges comparable to those described in the tears of dry eye patients shortens cell survival. Shioda et al. (p. 2916) show that exogenous taurine improves cell survival during such stress. Associated with this effect, these cells upregulate their Na+-dependent osmosensitive taurine transport activity up to nearly 4-fold. Underlying these increases, there are biphasic changes in taurine transporter gene and protein expression resulting in 4-fold increases in intracellular taurine. However, these increases are too small for taurine to serve as a significant osmolyte. Taurine may instead provide a membrane stabilizer or an antioxidant effect.
Apomorphine and Blink Control
Dopaminergic pathways have been implicated in normal blinking and pathologic blink conditions such as benign essential blepharospasm. Baker et al. (p. 2933) found that apomorphine normalized the dramatically up-regulated blink velocity and main sequence relationship on the normal side of the primate with facial nerve palsy. Normal animals showed longer faster blinks after apomorphine, and main sequence relationship, although tending to be lower, was not statistically different from baseline. These findings suggest that specific D-1 and D-2 agonists and antagonists may have a therapeutic role in abnormal blink motor control.
m-CSF in Ocular Cicatricial Pemphigoid
Macrophage accumulation in the submucosa is an important histologic feature of ocular cicatricial pemphigoid (OCP). Razzaque et al. (p. 2977) have shown that conjunctival fibroblast-derived macrophage colony-stimulating factor (m-CSF) plays a role in the accumulation of macrophages in conjunctiva of OCP patients; interleukin (IL)-1a and tumor necrosis factor (TNF)-a induces expression of m-CSF by conjunctival fibroblasts. Increased expression of m-CSF may augment or enhance local inflammatory responses in the conjunctiva of OCP patients. Therapeutic modulation of m-CSF production by conjunctival fibroblasts may alter the disease process.
IL-4, -13 in Ocular Allergy
Berger et al. (p. 2992) utilize a well-established model of keratitis to examine the regulatory role of IL-4 and IL-13 in recruitment of eosinophils. They demonstrated that blockade of IL-4, IL-13/receptor interactions in vivo has a significant effect on eosinophil infiltration into the cornea by inhibiting expression of ICAM-1 on limbal vessels. This may be a feasible approach to immunotherapy of ocular allergy.
Adenosine Receptors and IOP
The responses of intraocular pressure (IOP) in the mouse to selective drugs has previously suggested that A3 adenosine receptors (ARs) modulate IOP, despite methodological limitations arising from the difficulty in measuring drug concentrations in mouse aqueous humor and from possible species differences in responses to purinergic drugs. Here, mouse IOP was measured with the reliable servo-null micropipette system. Knockout of A3ARs lowered IOP and markedly reduced the effects of adenosine and the highly specific A3AR antagonist MRS 1191. The findings by Avila et al. (p. 3021) unequivocally establish the importance of A3ARs in regulating IOP and suggest a novel approach for treating glaucoma.
Preconditioning, Retinal Apoptosis and Ischemia
Ischemic preconditioning (IPC) has been shown to protect the rat retina against injury following ischemia. Zhang et al. (p. 3059) demonstrate that this protection involves the attenuation of apoptosis, a major mechanism of retinal cell death. Alterations in protein phosphorylation and expression of caspases were also blocked by IPC. The results suggest that stimulating endogenous mechanisms to prevent apoptotic cell death after ischemia should be further explored to prevent ischemic damage in humans.
Non-Invasive, Non-Viral Gene Therapy
Gene therapy of retinal diseases is optimized by widespread delivery of the therapeutic gene to the entire retina, retinal pigment epithelium, or other ocular structures. As reported in Zhu et al. (p. 3075), this is possible, without viral vectors, using gene targeting technology. The therapeutic gene is encapsulated within a lipid nanocontainer, which is administered intravenously. The nanocontainer loaded with therapeutic gene is decorated with receptor-specific monoclonal antibodies, and these antibodies trigger transcytosis across the blood-retinal barrier and endocytosis into cells of the eye. The site of gene expression within the eye can be regulated with tissue-specific gene promoters.
Glutamate and Diabetic Müller Cells
In the diabetic retina, the extracellular concentration of glutamate is elevated. Identifying causes for this disruption of glutamate homeostasis is important because excess levels of this neurotransmitter threaten sight by exacerbating oxidative stress and killing neurons. Li and Puro (p. 3109) now report that soon after the onset of experimental diabetes, the uptake of glutamate by Müller cells, the principal glia of the retina, is markedly decreased. However, glutamate transporter activity could be promptly restored with exposure of diabetic Müller cells to a chemical reductant. These new observations indicate the feasibility of using a pharmacological approach to limit complications of diabetic retinopathy by maintaining glial function.
BCA and PVR
Proliferative vitreoretinopathy (PVR) is a major cause of failure of retinal reattachment surgery, at least partially due to proliferations of retinal pigment epithelial cells (RPE cells). Lee et al. (p. 3117) show that 2-benzoyl-oxycinnamaldehyde (BCA) induced apoptosis in a rabbit PVR model. Modulation of p53, Akt and Bcl-2 phosphorylation was observed. No evidence of retinal toxicity was found even at 600 µM concentration. Thus, BCA might be an effective and safe inhibitor of RPE cells and have therapeutic value for BPR.
Triamcinolone and Exudative Retinopathy
Glucocorticoids are known to differentially mediate anti-angiogenic, anti-inflammatory and permeability effects. Triamcinolone (TA), an anti-inflammatory glucocorticoid, has been used in independent clinical studies as a potential therapy for exudative retinopathy, although its mode of action on human choroidal endothelial cells has not been completely defined. Using cultured human choroidal endothelial cells as a model for choroidal neovascular membranes, Penfold et al. (p. 3125) demonstrate that TA is able to reduce adhesion molecule expression and permeability, confirming its potential as a therapeutic agent for the treatment of exudative retinopathy.
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