Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies.

Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor-ß (TGF-ß) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-ß signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.

Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration: a pilot study.

PURPOSE: To evaluate whether bromfenac eyedrops and ranibizumab intravitreal injections would provide added efficacy over ranibizumab alone. METHODS: This was a single-site, multiinvestigator, prospective, open-label, interventional, Phase II study of patients with new or recurrent exudative/neovascular age-related macular degeneration. Thirty eyes were enrolled consecutively and were randomized in a ratio of 2:1 to combination therapy with intravitreal ranibizumab and topical bromfenac, and ranibizumab alone. All patients received ranibizumab monthly therapy for 4 months then as needed monthly in accordance with standard of care. Patients receiving bromfenac self-administered 1 drop twice a day for 12 months. Patients were followed for 12 months. RESULTS: There were no safety concerns with the combination therapy. No statistically significant differences were identified in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity or the number of injections required. However, the mean 12-month change in central macular thickness in the combination group was -81.56 µm while in the ranibizumab group alone the change was -42.50 µm (P = 0.03). The proportion of eyes experiencing a decrease in CMT of 50 µm or more was also significantly higher in those receiving combination therapy (P = 0.046). CONCLUSION: This pilot study is the first to prospectively identify a biologic signal that may indicate combination therapy with an easily administered well-tolerated eyedrop and ranibizumab is efficacious for the treatment of neovascular age-related macular degeneration. Further studies are warranted to validate this finding.

Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.

Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.

X-linked cataract and Nance-Horan syndrome are allelic disorders.

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

A novel 1-bp deletion in PITX3 causing congenital posterior polar cataract.

PURPOSE: Cataracts are the most common cause of blindness worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report a novel mutation in the paired-like homeodomain 3 (PITX3) gene segregating in a four generation English family with an isolated autosomal dominant posterior polar cataract. METHODS: A genome-wide linkage was performed by means of single nucleotide polymorphism (SNP) and microsatellite markers. Linkage analyses were performed with the GeneHunter and MLINK programs. Direct sequencing of PCR products was performed to detect mutation in the gene, using the BigDye version 3.1 and analyzed using Sequence analysis version 5.2. RESULTS: Genome-wide linkage analysis with SNP markers, identified a disease-haplotype interval on chromosome 10q. Two point positive logarithm of odds (LOD) scores was obtained with markers D10S205 (Z=3.10 at θ=0.00), flanked by markers D10S1709 and D10S543, which harbors the homeobox gene PITX3. Sequence analysis of PITX3 revealed a 1-bp deletion that cosegregated with all the affected members of this family which resulted in a frameshift in codon 181 and likely to produce an aberrant protein consisting of 127 additional residues. CONCLUSIONS: The 542delC is a novel mutation in PITX3 causing an isolated posterior polar cataract.

Rhesus monkeys and humans share common susceptibility genes for age-related macular disease.

Age-related macular degeneration (AMD), a complex multigenic disorder and the most common cause of vision loss in the elderly, is associated with polymorphisms in the LOC387715/ARMS2 and HTRA1 genes on 10q26. Like humans, macaque monkeys possess a macula and develop age-related macular pathologies including drusen, the phenotypic hallmark of AMD. We genotyped a cohort of 137 unrelated rhesus macaques with and without macular drusen. As in humans, one variant within LOC387715/ARMS2 and one in HTRA1 were significantly associated with affected status. HTRA1 and the predicted LOC387715/ARMS2 gene were both transcribed in rhesus and human retina and retinal pigment epithelium. Among several primate species, orthologous exons for the human LOC387715/ARMS2 gene were present only in Old World monkeys and apes. In functional analyses, the disease-associated HTRA1 polymorphism resulted in a 2-fold increase in gene expression, supporting a role in pathogenesis. These results demonstrate that two genes associated with AMD in humans are also associated with macular disease in rhesus macaques and that one of these genes is specific to higher primates. This is the first evidence that humans and macaques share the same genetic susceptibility factors for a common complex disease.

Progression of geographic atrophy and genotype in age-related macular degeneration.

PURPOSE: We sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Prospective analysis of participants in a randomized controlled clinical trial. PARTICIPANTS: We included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). METHODS: Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. MAIN OUTCOME MEASURES: Genotype frequencies and change in cumulative area of GA. RESULTS: The mean growth rate of GA for the 114 eyes was 1.79 mm(2)/year (range, 0.17-4.76). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value = 0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. CONCLUSIONS: Growth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association.

Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population.

PURPOSE: To estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort. METHODS: We genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed. RESULTS: The linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP. CONCLUSIONS: This is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.

CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration.

OBJECTIVE: To determine if CFH and LOC387715/ARMS2 genotypes influence treatment response to AREDS-type nutritional supplementation with antioxidants and zinc. DESIGN: Retrospective analysis of participants in a randomized, controlled clinical trial, the Age-Related Eye Disease Study (AREDS). PARTICIPANTS AND/OR CONTROLS: Eight hundred seventy-six AREDS study participants who were considered at high risk for developing advanced age-related macular degeneration (AMD). METHODS: Using DNA extracted from venous blood of 876 white participants in AREDS categories 3 and 4, that is, those considered to be at high risk for progression to advanced AMD, the authors genotyped for the single nucleotide polymorphisms in the CFH (Y402H, rs1061170) and LOC387715/ARMS2 (A69S, rs10490924) genes. The authors performed adjusted unconditional logistic regression analysis and assessed interactions of these genotypes to determine the relationship between CFH and LOC387715/ARMS2 genotype and treatment with antioxidants plus zinc. MAIN OUTCOME MEASURES: Interaction between genetic variants and treatment response as determined by progression from high-risk to advanced AMD. RESULTS: Progression occurred in 264 of 876 patients from AREDS category 3 (intermediate AMD) to category 4 or 5 (unilateral or bilateral advanced AMD, respectively), or from category 4 to category 5. A treatment interaction was observed between the CFH Y402H genotype and supplementation with antioxidants plus zinc (CC; P = 0.03). An interaction (P = 0.004) was observed in the AREDS treatment groups taking zinc when compared with the groups taking no zinc, but not in groups taking antioxidants compared with those taking no antioxidants (P = 0.59). There were no significant treatment interactions observed with LOC387715/ARMS2. CONCLUSIONS: The findings of this study indicate that an individual's response to AREDS supplements may be related to CFH genotype. This could have clinical relevance by predicting treatment outcome and potentially preventing unwanted side effects in those who may not benefit. Corroboration of these analyses is needed before considering modification of current management. This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment.

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa: A Randomized Phase 2 Multicenter Placebo-Controlled Clinical Trial.

Importance: There are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness. Objectives: To evaluate the potential efficacy and assess the safety of orally administered valproic acid (VPA) in the treatment of autosomal dominant retinitis pigmentosa. Design, Setting, and Participants: Multicenter, phase 2, prospective, interventional, placebo-controlled, double-masked randomized clinical trial. The study took place in 6 US academic retinal degeneration centers. Individuals with genetically characterized autosomal dominant retinitis pigmentosa were randomly assigned to receive treatment or placebo for 12 months. Analyses were intention-to-treat. Interventions: Oral VPA 500 mg to 1000 mg daily for 12 months or placebo. Main Outcomes and Measures: The primary outcome measure was determined prior to study initiation as the change in visual field area (assessed by the III4e isopter, semiautomated kinetic perimetry) between baseline and month 12. Results: The mean (SD) age of the 90 participants was 50.4 (11.6) years. Forty-four (48.9%) were women, 87 (96.7%) were white, and 79 (87.8%) were non-Hispanic. Seventy-nine participants (87.8%) completed the study (42 [95.5%] received placebo and 37 [80.4%] received VPA). Forty-two (46.7%) had a rhodopsin mutation. Most adverse events were mild, although 7 serious adverse events unrelated to VPA were reported. The difference between the VPA and placebo arms for mean change in the primary outcome was -150.43 degree2 (95% CI, -290.5 to -10.03; P = .035). Conclusions and Relevance: This negative value indicates that the VPA arm had worse outcomes than the placebo group. This study brings to light the key methodological considerations that should be applied to the rigorous evaluation of treatments for these conditions. This study does not provide support for the use of VPA in the treatment of autosomal dominant retinitis pigmentosa. Trial Registration: ClinicalTrials.gov Identifier: NCT01233609.

Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.

[This corrects the article DOI: 10.1371/journal.pone.0025598.].

Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration.

CONTEXT: Studies have reported that single-nucleotide polymorphisms in the genes CFH and LOC387715 are associated with age-related macular degeneration (AMD). OBJECTIVE: To assess whether these genetic variants have prognostic importance for progression to advanced AMD and related visual loss. DESIGN, SETTING, AND PARTICIPANTS: Prospective analysis of 1466 white participants in the Age-Related Eye Disease Study (AREDS), a US multicenter clinical trial conducted from 1990 to 2001 with a mean follow-up time of 6.3 years. Age-related macular degeneration status was determined by grading of fundus photographs. Progression (n = 281) was defined as newly diagnosed advanced AMD (geographic atrophy, exudative disease, or AMD causing visual loss) in one or both eyes during the course of the study. Genotypic analysis was conducted in 2006. MAIN OUTCOME MEASURE: Incidence rates of dry and neovascular advanced AMD. RESULTS: The CFH Y402H and LOC387115 A69S polymorphisms were each independently related to progression from early or intermediate stages to advanced stages of AMD, controlling for demographic factors, smoking, body mass index, and AREDS vitamin-mineral treatment assignment, with odds ratios (ORs) of 2.6 (95% confidence interval [CI], 1.7-3.9) for CFH and 4.1 (95% CI, 2.7-6.3) for LOC387715 for the homozygous risk genotypes (P<.001 for trend for each additional risk allele for both genes). The effect of LOC387715 was stronger for progression to neovascular disease (OR, 6.1; 95% CI, 3.3-11.2) compared with geographic atrophy (OR, 3.0; 95% CI, 1.4-6.5) relative to no progression for the homozygous risk state. The presence of all adverse factors (both risk genotypes, smoking, and body mass index > or =25) increased risk 19-fold. Smoking and high body mass index increased odds of progression within each risk genotype. Genetic plus nongenetic risk scores provided an area under the receiver operating characteristic curve of up to 0.78. CONCLUSIONS: Common polymorphisms in the genes CFH and LOC387715 are independently related to AMD progression after adjustment for other known AMD risk factors. Presence of these polymorphisms plus smoking [corrected] and body mass index of 25 or higher, controlling for AREDS vitamin-mineral treatment, identifies [corrected] patients who are highly susceptible to developing advanced states [corrected] of this visually disabling disease.

Expanded genome scan in extended families with age-related macular degeneration.

PURPOSE: To investigate further the genetic contribution to age-related macular degeneration (AMD), increasing the power of a previous analysis and reproducing the original findings. METHODS: A large cohort of families with this condition was assembled, and an expanded genome scan was performed with 556 microsatellite markers. In 2003, the results were reported of a genome-wide linkage analysis of 70 of these pedigrees. Members of 51 new families have now been ascertained and many of the original pedigrees expanded. Parametric and nonparametric linkage analyses were performed with a denser map of markers. In addition, analyses were performed with the sample stratified by age at ascertainment and by two major advanced phenotypes for the disease: neovascular AMD (choroidal neovascularization) and geographic atrophy. RESULTS: The results corroborate the macular degeneration-susceptibility loci consistently reported by the authors and others in genome-wide scans. New loci were identified, including the finding of a two-point HLOD of 3.70 at 6q25.2. CONCLUSIONS: The results suggest that the use of families enriched in predisposition to AMD has legitimacy. Genetic analyses of a genome-wide scan performed on our large cohort of families add further confirmatory evidence that susceptibility loci lie on 1q, 3p, 9q, and 10q. Furthermore, new loci have been identified, including a locus on 6q.

Photodynamic therapy of subfoveal choroidal neovascularization secondary to reticular pattern dystrophy: three-year results of an uncontrolled, prospective case series.

PURPOSE: To investigate the effects of photodynamic therapy (PDT) on subfoveal choroidal neovascularization (CNV) secondary to reticular pattern dystrophy (RPD) of the retinal pigment epithelium. DESIGN: Open-label, prospective, interventional case series. METHODS: Thirteen eyes diagnosed with subfoveal CNV associated with RPD were considered. Complete ophthalmic examinations were performed at baseline and thereafter at three-month intervals for three years. Primary outcome measure was the number of eyes with <15 letters loss (approximately <3 lines) at 12, 24, and 36 months, compared with baseline. Secondary outcome measures included CNV progression and number of PDT sessions. RESULTS: Seven eyes showed a decrease in best-corrected visual acuity of at least three lines at three-year examination. Each eye received a median number of treatments of two, zero, and zero in years one, two, and three, respectively. CONCLUSIONS: PDT does not appear to guarantee long-term vision stabilization in RPD-related subfoveal CNV, and alternative therapies should be investigated.

VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry.

PURPOSE: To analyze static visual field sensitivity with topographic models of the hill of vision (HOV), and to characterize several visual function indices derived from the HOV volume. METHODS: A software application, Visual Field Modeling and Analysis (VFMA), was developed for static perimetry data visualization and analysis. Three-dimensional HOV models were generated for 16 healthy subjects and 82 retinitis pigmentosa patients. Volumetric visual function indices, which are measures of quantity and comparable regardless of perimeter test pattern, were investigated. Cross-validation, reliability, and cross-sectional analyses were performed to assess this methodology and compare the volumetric indices to conventional mean sensitivity and mean deviation. Floor effects were evaluated by computer simulation. RESULTS: Cross-validation yielded an overall R2 of 0.68 and index of agreement of 0.89, which were consistent among subject groups, indicating good accuracy. Volumetric and conventional indices were comparable in terms of test-retest variability and discriminability among subject groups. Simulated floor effects did not negatively impact the repeatability of any index, but large floor changes altered the discriminability for regional volumetric indices. CONCLUSIONS: VFMA is an effective tool for clinical and research analyses of static perimetry data. Topographic models of the HOV aid the visualization of field defects, and topographically derived indices quantify the magnitude and extent of visual field sensitivity. TRANSLATIONAL RELEVANCE: VFMA assists with the interpretation of visual field data from any perimetric device and any test location pattern. Topographic models and volumetric indices are suitable for diagnosis, monitoring of field loss, patient counseling, and endpoints in therapeutic trials.

Molecular genetic basis of inherited cataract and associated phenotypes.

Congenital cataract is a leading cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents a significant proportion of cases and recently many causative genetic mutations have been identified. Inherited cataract is known to be clinically and genetically heterogeneous. Eleven clear-cut cataract phenotypes have been described. Cataract may be inherited as autosomal dominant, autosomal recessive, or X-linked recessive traits, and 12 loci and 15 specific genes associated with inherited isolated cataract have been identified to date; it is likely that more genes remain to be discovered. The identification of remaining genes will not only improve our understanding of the mechanism of cataract formation but will shed new light on the developmental biology and biochemistry of the lens. Furthermore, it is possible that some of these genes will be implicated in the more common age related cataract, which also has a genetic component to its etiology.

Genetics of age-related macular degeneration.

Gene discoveries will lead to more effective them pies for AMD by identifying specific underlying disease mechanisms that might be corrected by drugs or gene therapy. For example, investigations are currently being carried out using pigment epithelium-derived factor (FEDF). The gene for this potent inhibitor of angiogenesis has been incorporated into an adenoviral vector and delivered into the eye by intravitreal injection to inhibit growth of new blood vessels in eyes with neovascular AMD. In the future, as the genetics of this complex disease are unraveled, more effective treatments and preventative measures that target specific molecular defects underlying the development of AMD can be expected.

Gene therapy and control of angiogenesis.

The technology of gene therapy may be one step ahead of the present understanding of angiogenesis. The results of studies to modulate angiogenesis have been encouraging, however, and several of these studies are in the preclinical and clinical phases of testing. It is likely, therefore, that gene therapy for such diseases as diabetes mellitus and age-related macular degeneration will soon become a practical reality. It must be hoped that the lessons learned will be beneficial to others attempting to modulate angiogenesis in systemic disorders such as cancer and rheumatoid arthritis.