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| April 2003 | Inside IOVS | Volume 44/4 |
X-Linked Retinitis Pigmentosa
Mutations in the X-chromosomal RPGR gene account for up to 20% of all cases of retinitis pigmentosa. This high degree of sequence variation is due to a large 3' terminal exon (ORF15) of an alternatively spliced RPGR transcript predominantly expressed in retina. Bader et al. (p. 1458) screened 58 xlRP families for mutations in the RPGR and the RP2 gene and found that 63% of families with definite X-linkage had a mutation in RPGR exon ORF15. A high frequency and a wide range of in-frame sequence alterations in controls show that mutation analysis in RPGR exon ORF15 remains challenging.
Results of the Correction of Myopia Evaluation Trial
As reported in Gwiazda et al. (p. 1492), the Correction of Myopia Evaluation Trial (COMET), a randomized, multi-center clinical trial based in four colleges of optometry in the United States, evaluated the effect of progressive addition lenses (PALs with a +2.00 addition) compared to single vision lenses (SVLs) on the progression of juvenile-onset myopia. COMET enrolled 469 ethnically diverse 6-11 year old children with moderate myopia within one year. Retention of children was outstanding, with 98.5% completing the 3-year visit. The 3-year difference between the two treatment groups in myopia progression determined by cycloplegic autorefraction, the primary outcome, was 0.20 ± 0.08 D (P = 0.004). This was paralleled by a 3-year difference in axial length of 0.11 ± 0.03 mm (P = 0.0002). The treatment effect was observed primarily during the first year. A larger effect of PALs was observed in children with lower versus higher baseline accommodation at near (P = 0.03), and lower versus higher baseline myopia (P = 0.04), providing some support for the COMET rationale, i.e., a role for defocus in myopia progression. The small magnitude of the treatment effect does not warrant a change in clinical practice.
Gene Delivery to Lacrimal Glands Ex-Vivo
Gene transfer to the lacrimal gland could potentially be a means to modify tear composition or volume of tear secretion. Banin et al. (p. 1529) examined the feasibility of gene delivery into lacrimal gland tissue in organotypic culture. Two viral vectors, vaccinia and adenovirus (but not herpes virus), were found efficient for reporter gene transfer in this model. Specific gene expression patterns were observed: with the vaccinia vector, lacrimal duct cells were predominantly infected, while the adenoviral vector tended to transduce the interacinar areas, in particular the myoepithelial cells. This may be the first step towards expressing genes whose products could be continuously delivered to the eye via the tears.
Corticosteroids Regulate Aqueous Humor Production
Corticosteroids are known to play a fundamental role in epithelial sodium transport in tissues such as the kidney, where the serum and glucocorticoid regulated kinase isoform 1 (SGK1) has recently been identified as an early gene involved in the activation of pre-existing epithelial sodium channels (ENaC). In this issue, Rauz et al. (p. 1643) demonstrate expression of SGK1 and ENaC subunits in the human ocular ciliary epithelium, and confirm mineralocorticoid and glucocorticoid regulation of SGK1 in the non-pigmented ciliary epithelium. These data indicate that this mechanism may be an integral feature of ciliary epithelial sodium transport, and therefore aqueous humor production, providing a novel target for the pharmacological management of glaucoma.
Retinal Transplants Recover Retino-Tectal Vision in a Rodent Retinal Degeneration Model
Sagdullaev et al. (p. 1686) demonstrate that transplantation of fetal retina into the subretinal space of a rat model of retinal degeneration induces recovery of visual responses in the brain. While the underlying mechanism remains to be elucidated, these results show that visual function is recovered, not simply preserved, and that this recovery is induced by the transplant. Thus, retinal transplantation could be used to restore visual activity in the retinitis pigmentosa syndromes and other human retinal degenerations.
Bruch’s Membrane Forms a Lipid Barrier
Quick-freeze/deep-etch and conventional techniques were used to prepare macular Bruch's membrane from four normal human eyes (aged 27, 41, 76 and 78) for electron microscopic examination. The results reported in Ruberti et al. (p. 1753) suggest that the predilection of an extremely thin sublayer of inner Bruch's membrane for accumulating lipid particles may eventually lead to the formation of a confluent "lipid wall" capable of isolating the retina from its blood supply. This may be an important early stage in the pathogenesis of age-related maculopathy.
Involvement of Serine Proteinases in CNV
Genetically altered mice may reveal unanticipated roles for previously characterized proteinases. Using a laser-induced model of choroidal neovascularization in deficient mice, Rakic et al. (p. 1732) have demonstrated that members of the plasminogen activator system are involved in the development of pathological angiogenesis under the retina. Control of the fibrinolytic activity could therefore represent an additional strategy, in combination with other inhibitors, for the treatment of the exudative form of age-related macular degeneration.
Retinal Blood Flow during Diabetic Pregnancy
In this study by Loukovaara et al. (p. 1486), perimacular capillary blood flow was measured in 32 pregnant women with insulin-dependent diabetes and 11 non-diabetic pregnant women by Heidelberg Retinal Flowmetry throughout pregnancy and postpartum. The flow values were higher in diabetic women during pregnancy, compared to non-diabetic pregnant women or non-pregnant diabetic women. In patients with mostly minimal to moderate retinopathy, no clear correlation between flow values and progression of retinopathy could be observed. These results indicate that retinal capillary blood flow responds to pregnancy in a different manner in diabetics compared to non-diabetics. This may be related to impaired autoregulation of capillary blood flow in diabetes.
Functional and Structural Improvement in Gene Therapy Treated Dogs
In the study by Narfström et al. (p. 1663), gene therapy was utilized in a large group of RPE65 null mutation dogs with severe, early onset visual impairment or blindness, similar to Leber’s congenital amaurosis. Subretinal injections of an adeno-associated virus (rAAV).RPE65 gene construct resulted in substantially improved vision and electroretinographic responses, the latter up to 32% ERG amplitudes in normal dogs. No systemic adverse effects were found, but 75% of the transgene treated eyes developed uveitis. Morphologic studies showed a reversal of pathologic changes in the RPE in the area of treatment. These results give further evidence that gene transfer therapy in the eye is effective but also demonstrates a local side effect that needs to be investigated.
Ultrahigh Resolution OCT versus Histology
Ultrahigh resolution OCT of the fresh pig retinas is compared to histology using differential inter-ference contrast microscopy to evaluate the potential of this novel generation of OCT for enhanced visualization of intra- and subretinal structures. As reported in Gloesmann et al. (p. 1696), in vitro ophthalmic ultrahigh resolution OCT imaging reveals retinal mor-phology with unprecedented detail and provides a basis for improved interpretation of in vivo ophthalmic OCT tomo-grams of high clinical relevance.
ERK-1 and -2 in Retinal Angiogenesis
Investigations by Bullard et al. (p. 1722) have focused on ERK-1 and -2 as important branch points in VEGF signal transduction. The authors have demonstrated that ERK activation plays a critical role in VEGF-induced endothelial cell (EC) proliferation, but not in VEGF-induced differentiation of EC into capillary tubes. This is particularly important in the context of retinopathy of prematurity where EC proliferation drives the formation of pathologic pre-retinal vessel growth, while differentiation plays a more important role in the simultaneous growth of normal, intraretinal vessels. A therapeutic strategy that targets ERK may, thus, address pathologic vessel growth at the same time as it permits normal retinal vasculogenesis.
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