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Inside IOVS 2001
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September 2001 |
Ocular Diseases: Genes, Incidence and Treatments
Nasal Antimicrobials
The study by Paulsen et al. (p. 2157) compares antimicrobial peptides at work on the mucosal side of the lacrimal passage between body donors and biopsies from inflamed patient mucosa. The results suggest that the human nasolacrimal ducts produce a spectrum of antimicrobial peptides including the human inducible defensin HBD-2. The production of several antimicrobial peptides leads to synergistic and additive killing effects. Possibly purified or recombinant antimicrobial peptides, especially inducible, may be ideal agents in the therapy of dacryocystitis when applied to the site of infection.
Glaucoma Genes in Japan
CYP1B1 gene (GLC3A locus) mutations were associated with over 85% of primary congenital glaucoma (PCG) families in Saudi Arabia, Turkey and Slovakia where consanguineous marriages commonly occur. Mashima et al. (p. 2211) screened 65 unrelated Japanese patients with sporadic occurrence of PCG. None of the patients was an offspring of a consanguineous marriage. Eleven novel mutations of the CYP1B1 gene were detected in 13 (20%) of the 65 patients. CYP1B1 gene mutations in sporadic occurrence of PCG represent an allelic heterogeneity and may be unique to a specific population. There may be a second PCG locus (GLC3B) in the Japanese population.
Disease Severity in RP
All mutations identified in the RP1 gene causing retinitis pigmentosa (RP) are dominant, and they all lead to predicted proteins that lack one half to two thirds of the carboxy terminus. The results by Berson et al. (p. 2217) suggest that the remaining amino-terminal fragment of the protein has a yet-to-be-defined toxic effect on photoreceptors. The severity of disease caused by RP1 mutations is similar to that produced by dominant rhodopsin mutations and an observed 100-fold variation in severity suggests that other genetic or environmental factors powerfully affect the course of retinal degeneration.
AMD Incidence: Europe vs. USA
The population-based Rotterdam Study by Klaver et al. (p. 2237) provides evidence that age-related maculopathy (ARM) occurs at a lower incidence in the Netherlands than in the United States. The disease profile is not different from the American studies. Total drusen area and the presence of pigmentary changes are the most prognostic features for progression to ARM end stages, and phenotypes appear to be very similar. Since it has been shown that well-known risk factors such as smoking and vascular factors do not explain the frequency differences, it remains intriguing to identify the origin of this difference. Future identification of such factors may open up possibilities of disease prevention.
Corneal SP ± IGF-1 Treatment
Spontaneous chronic corneal epithelial defects (SCCED) are commonly encountered in humans and dogs. Murphy et al. (p. 2252) describe the clinical features, alterations in peptidergic innervation, modulation of substance P (SP) content and response to treatment with SP ± IGF-1 of SCCED in dogs. The defects had been present an average of 9 weeks (range, 3-52). Peptidergic innervation was markedly altered in affected dogs with an increase in SP and CGRP-containing fibers peripheral to the denuded area. Topical treatment with SP ± IGF-1 resulted in complete healing in 70-75% of patients in 2-3 weeks.
SOD and Keratoconus
The human cornea contains high levels of the interstitially located extracellular superoxide dismutase (SOD). Behndig et al. (p. 2293) discovered that the levels of this extracellular superoxide radical scavenger are halved in corneas from keratoconus patients, whereas they are normal in bullous keratopathy. The extracellular SOD levels are also halved in corneal transplants removed before retransplantation of former keratoconus patients, but not of former bullous keratopathy patients. This scavenger deficiency aligns well to recent hypotheses on keratoconus pathogenesis and might contribute to the development of the disease.
Neurotrophins and Glaucoma
One theory in the pathology of primary open angle glaucoma is that retinal ganglion cell death is due to a lack of neurotrophic support. Lambert et al. (p. 2315) examined the expression of neurotrophins (NGF, BDNF, NT-3 and NT-4) and neurotrophin receptors (trks) within human lamina cribrosa (LC) cells and tissue. The authors demonstrate neurotrophin (NT) and trk mRNA and protein expression, as well as NT secretion. This study suggests a potential NT source exists within the LC. It also provides a basis for the glaucomatous damage observed within the LC.
CNV Gene Therapy
Age-related macular degeneration (AMD) causes blindness as a result of the development of choroidal neovascularization (CNV) and overlying retinal damages. To suppress CNV formation by gene therapy, Lai et al. (p. 2401) injected recombinant adeno-associated virus carrying angiostatin gene (rAAV-angiostatin) into the subretinal space. Both histology analysis and fluorescein angiography revealed significant reduction of the size of laser-induced CNV lesions in injected eyes. This is the first report of effective gene therapy of CNV and it does not cause retina apoptosis or inflammation.
VEGF and Diabetes
The causal role of vascular endothelial growth factor (VEGF) in diabetic blood-retinal barrier breakdown is unknown. Qaum et al. (p. 2408) demonstrate that endogenous VEGF triggers early diabetic blood-retinal barrier breakdown in rats. This breakdown localizes to the venules and capillaries of the superficial inner retinal vasculature, and can be inhibited with VEGF TrapA40, a highly specific VEGF-neutralizing soluble receptor. In the future, VEGF inhibition may prove a useful therapeutic approach to the treatment of early diabetic blood-retinal barrier breakdown.
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