Recent developments in the management of dry age-related macular degeneration

Elisa Buschini, Antonio M Fea, Carlo A Lavia, Marco Nassisi, Giulia Pignata, Marta Zola, Federico M Grignolo Ospedale Oftalmico, Ophthalmic Section, Department of Clinical Pathophysiology, University of Turin, Turin, Italy Abstract: Dry age-related macular degeneration (AMD), also called geographic atrophy, is characterized by the atrophy of outer retinal layers and retinal pigment epithelium (RPE) cells. Dry AMD accounts for 80% of all intermediate and advanced forms of the disease. Although vision loss is mainly due to the neovascular form (75%), dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. Actual management consists of lifestyle modification, vitamin supplements, and supportive measures in the advanced stages. The Age-Related Eye Disease Study demonstrated a statistically significant protective effect of dietary supplementation of antioxidants (vitamin C, vitamin E, beta-carotene, zinc, and copper) on dry AMD progression rate. It was also stated that the consumption of omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, has protective effects. Other antioxidants, vitamins, and minerals (such as crocetin, curcumin, and vitamins B9, B12, and B6) are under evaluation, but the results are still uncertain. New strategies aim to 1) reduce or block drusen formation, 2) reduce or eliminate inflammation, 3) lower the accumulation of toxic by-products from the visual cycle, 4) reduce or eliminate retinal oxidative stress, 5) improve choroidal perfusion, 6) replace/repair or regenerate lost RPE cells and photoreceptors with stem cell therapy, and 7) develop a target gene therapy. Keywords: dry AMD, geographic atrophy, new AMD therap

Retinoblastoma-independent antiproliferative activity of novel intracellular antibodies against the E7 oncoprotein in HPV 16-positive cells

<p>Abstract</p> <p>Background</p> <p>"High risk" Human Papillomavirus strains are the causative agents of the vast majority of carcinomas of the uterine cervix. In these tumors, the physical integration of the HPV genome is a frequent, though not invariable occurrence, but the constitutive expression of the E6 and E7 viral genes is always observed, suggesting key roles for the E6 and E7 oncoproteins in the process of malignant transformation. The "intracellular antibody" technology using recombinant antibodies in single-chain format offers the possibility of targeting a protein in its intracellular environment even at the level of definite domains thus representing a valuable strategy to "knock out" the function of specific proteins.</p> <p>Methods</p> <p>In this study, we investigate the <it>in vitro </it>activity of two single-chain antibody fragments directed against the "high-risk" HPV 16 E7 oncoprotein, scFv 43M2 and scFv 51. These scFvs were expressed by retroviral system in different cell compartments of the HPV16-positive SiHa cells, and cell proliferation was analyzed by Colony Formation Assay and EZ4U assay. The binding of these scFvs to E7, and their possible interference with the interaction between E7 and its main target, the tumor suppressor pRb protein, were then investigated by immunoassays, PepSet™technology and Surface Plasmon Resonance.</p> <p>Results</p> <p>The expression of the two scFvs in the nucleus and the endoplasmic reticulum of SiHa cells resulted in the selective growth inhibition of these cells. Analysis of binding showed that both scFvs bind E7 via distinct but overlapping epitopes not corresponding to the pRb binding site. Nevertheless, the binding of scFv 43M2 to E7 was inhibited by pRb in a non-competitive manner.</p> <p>Conclusions</p> <p>Based on the overall results, the observed inhibition of HPV-positive SiHa cells proliferation could be ascribed to an interaction between scFv and E7, involving non-pRb targets. The study paves the way for the employment of specific scFvs in immunotherapeutic approaches against the HPV-associated lesions.</p

Vitrectomy in Small idiopathic MAcuLar hoLe (SMALL) study: conventional internal limiting membrane peeling versus inverted flap

\ua9 The Author(s), under exclusive licence to The Royal College of Ophthalmologists 2024. Background: To compare conventional internal limiting membrane (ILM) peeling versus inverted flap technique in small idiopathic macular hole. Methods: Retrospective, multicentre cohort study including consecutive eyes with a ≤250 μm idiopathic macular hole treated with primary vitrectomy. The primary outcome was best-corrected visual acuity (BCVA) change and macular hole closure rate. Closure patterns on optical coherence tomography (OCT) and rates of external limiting membrane (ELM) and ellipsoid zone (EZ) recovery were considered as secondary outcomes. Results: A total of 389 and 250 eyes were included in the conventional ILM peeling group and in the inverted flap group, respectively. Hole closure rate was comparable between the two groups (98.5% in the ILM peeling group and 97.6% in the inverted flap group). Mean BCVA was comparable between the two groups at baseline (p = 0.331). At 12 months, mean BCVA was 0.14 \ub1 0.19 logMAR in the conventional ILM peeling group and 0.17 \ub1 0.18 logMAR in the inverted flap group (p = 0.08). At 12 months, 73% of eyes had a U-shape closure morphology in the conventional ILM peeling group versus 55% in the inverted flap group. At 12 months, ELM recovery rate was 96% and 86% in the conventional ILM peeling group and in the inverted flap group, respectively (p &lt; 0.001); EZ recovery rate was 78% and 69%, respectively (p = 0.04). Conclusions: The inverted flap technique provides no advantages in terms of visual outcome and closure rate in small idiopathic macular hole surgery. Additionally, this technique seems to impair postoperative restoration of external retinal layers compared with conventional peeling

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10-15), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10-16), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10-14), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10-11), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10-12). We also confirmed significant association at three previously described loci (P < 5 × 10-8 for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG