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| May 2004 | Inside IOVS | Volume 45/5 |
Von Hippel-Lindau Tumor Suppressor Gene Inhibits Retinal Neovascularization
Akiyama et al. (p. 1289) present evidence that von Hippel-Lindau (VHL) tumor suppressor gene is successfully introduced into intraocular tissues by means of adenovirus-mediated gene delivery and is effective for inhibiting neovascularization associated with multiple branch retinal vein occlusions (BRVO) in monkeys. Because vascular endothelial growth factor (VEGF) expression is inhibited in adenovirus VHL-infected cells and ocular tissue, favorable effects of VHL gene delivery is partly due to the inhibition of VEGF expression. These data suggest that VHL gene therapy represents a potential treatment for neovascular diseases in human eyes.
Age-Related Macular Degeneration and Apolipoprotein E
An association between age-related macular degeneration (AMD) and apolipoprotein E (apoE) has been reported. Zareparsi et al. (p. 1306) analyzed apoE allele frequencies in 632 AMD patients and 206 controls of Caucasian ancestry. Gender- and age-adjusted odds ratios indicate that e4-carriers have significantly lower risk of developing AMD compared to e3e3 subjects (OR = 0.55, 95% CI: 0.37-0.82, P = 0.004). apoE alleles did not appear to modulate the age at diagnosis of AMD in our cohort. These studies consolidate the association between the apoE-e4 allele and a reduced risk of AMD in a large cohort with sufficient statistical power.
ApoE Alleles and AMD
The apolipoprotein (apoE) gene has been considered to be a genetic risk factor for age related macular degeneration (AMD). Baird et al. (p. 1311) confirmed the protective role for the e4 allele and found the greatest effect being in individuals with atrophic disease and in males. Intriguingly, individuals with the e2e3 genotype presented at an earlier age of diagnosis compared to those with the e3e3 genotype. These findings add further support for a role of this gene in AMD, but it remains to be determined how the alleles of apoE influence the disease outcome and why the allelic association appears opposite to that of other aging diseases.
Nonsurgical Risk Factors for Endophthalmitis after Cataract Surgery
Although operative procedures and practices are important determinants in surgical outcome, equally important are the systems of care. Li et al. (p. 1321) conducted a population-based study of endophthalmitis after cataract surgery, which revealed that an increased risk of this much feared complication occurred in patients over 80 years of age, with surgery in a private hospital, with concurrent lacrimal or eyelid procedures, and also to a lesser extent with same-day surgery and operations in winter. The model developed from these data suggests that it may be possible to reduce the incidence of endophthalmitis by almost 80%, highlighting the importance of systems in maintaining the quality of health care.
Hyperspectral Imaging Monitors Retinal Oxygenation Responses
Khoobehi et al. (p. 1464) describe a new imaging method for studies of retinal and optic nerve oxygenation in animal models. Maps of oxygen saturation changes in the retinal vessels and the optic nerve head at increased oxygen concentration and intraocular pressure were derived from spectral reflectance imagery. Results with this method were in agreement with known experimental outcomes and showed that profound desaturation accompanies high intraocular pressure. This study anticipates the utility of hyperspectral imaging to reveal altered oxygenation and blood flow in retinal diseases such as glaucoma and diabetic retinopathy.
Erythropoietin Protects Retinal Ganglion Cells from Programmed Cell Death
Erythropoietin (EPO) inhibits apoptosis of red blood cell progenitors. It is used for the treatment of anemia. EPO also protects neurons from programmed cell death. Weishaupt et al. (p. 1514) found that EPO protected rat retinal ganglion cells from apoptosis following optic nerve transection and also had a preventive effect on neuronal cell death due to neurodegenerative disorders such as Parkinson’s or Alzheimer’s disease. The authors delineate the intracellular signalling pathways transmitting these effects. Their data establish EPO as a potential drug therapy for glaucoma, as well as for the predominantly apoptotic neuronal cell death in the context of neurodegenerative diseases.
Reduced Endostatin Levels in Age-Related Macular Degeneration
Ocular blood vessels are normally quiescent and rarely grow in postnatal life. The balance between angiogenic and anti-angiogenic factors is thought to maintain this quiescent state. If this state is disturbed, angiogenesis (new blood vessel growth) occurs. Endostatin, a proteolytic fragment of collagen XVIII, is one of the endogenous anti-angiogenic factors that may be part of this balance. Bhutto et al. (p. 1544) find that endostatin is reduced in the RPE/Bruch’s membrane/choriocapillaris complex of subjects with age-related macular degeneration (AMD) compared to control subjects. However, collagen XVIII is comparable in the two groups. This reduction in the endostatin portion of collagen XVIII in AMD subjects may be permissive for angiogenesis.
Modulation of Sub-RPE Deposits In Vitro: a Potential Model for Age-Related Macular Degeneration
Deposits seen beneath the retinal pigment epithelium (RPE) form in a variety of conditions, most notably in age-related macular degeneration. Amin et al. (p. 1281) generated sub-RPE deposits in vitro. RPE cells were grown in culture with media containing various compounds and the amount of deposit was assessed by electron microscopy. The results demonstrated that sub-RPE deposits formed in vitro share ultrastructural features with those seen in vivo. Challenges with both albumin and retinal homogenate led to a greater net deposit formation, while cells treated with TNF-a or MMP-2 showed a reduction in sub-RPE deposits. Significantly the results provide a proof of principle that sub-RPE deposits can be formed and modified in vitro. This modulation has both clinical and therapeutic implications.
Specific Gene Transfer to the Trabecular Meshwork
Gonzalez et al. (p. 1389) show that the promoter from the matrix Gla protein gene can direct transgene expression specifically to the cells of the outflow pathway in gene transfer experiments using recombinant adenoviruses. These results show the feasibility of using specific promoters to target gene expression to the outflow pathway cells. Strategies focused on gene delivery both for experimental purposes as well as for gene therapy of glaucoma can benefit from such specific targeted expression to the cells of interest, avoiding expression in other cells of the anterior segment that can complicate experimental interpretation or result in undesirable secondary effects.
Reliably Detecting Glaucoma Progression
In glaucoma there is an insiduous and progressive loss of optic nerve neurones which is notoriously difficult to detect. Standard clinical tests for progression are subjective, prone to variability, and their usefulness is difficult to confirm for lack of a gold standard. Tan and Hitchings (p. 1396) have devised a method to detect glaucomatous morphological change by longitudinally modeling the complex topography of the optic nerve head in images derived by in vivo scanning laser tomography. We find that this method reliably distinguishes progressing from unchanging eyes. It is objective, can be automated in software, and could find application in patient care and research into glaucoma treatments.
Pyruvate Protection of Retina against Ischemia
As in other areas of the central nervous system, the retina contains a releasable pool of zinc. Consistent with the role of endogenous zinc in retinal neuronal death, Yoo et al. (p. 1523) have found that zinc accumulates in degenerating neuronal cells after pressure-induced ischemia in rats. In retinal cell cultures, zinc-induced cell death was mediated by poly (ADP-ribosyl) polymerase (PARP) and prevented by pyruvate. Consistent with the results obtained in cell culture, pyruvate substantially reduced retinal neuronal death in rats following pressure-induced ischemia. Since pyruvate is an innocuous endogenous metabolite of glucose, pyruvate may prove useful as a neuroprotectant in human retinal ischemia.
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