Ocular delivery of Pigment Epithelium-Derived Factor (PEDF) as a neuroprotectant for Geographic Atrophy.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), that starts with atrophic lesions in the outer retina that expand to cover the macula and fovea, leading to severe vision loss over time. Pigment Epithelium-Derived Factor (PEDF) has a diverse-range of properties, including its ability to promote cell survival, reduce inflammation, inhibit angiogenesis, combat oxidative stress, regulate autophagy, and stimulate anti-apoptotic pathways, making it a promising therapeutic candidate for GA. However, the relatively short half-life of PEDF protein has precluded its potential as a clinical therapy for GA since it would require frequent injections. Therefore, we describe administration of a PEDF gene, comparing and contrasting delivery routes, viral and non-viral vectors, and consider the critical challenges for PEDF as a neuroprotectant for GA.

A synthetic lethal screen identifies a role for the cortical actin patch/endocytosis complex in the response to nutrient deprivation in Saccharomyces cerevisiae.

Saccharomyces cerevisiae whi2Delta cells are unable to halt cell division in response to nutrient limitation and are sensitive to a wide variety of stresses. A synthetic lethal screen resulted in the isolation of siw mutants that had a phenotype similar to that of whi2Delta. Among these were mutations affecting SIW14, FEN2, SLT2, and THR4. Fluid-phase endocytosis is severely reduced or abolished in whi2Delta, siw14Delta, fen2Delta, and thr4Delta mutants. Furthermore, whi2Delta and siw14Delta mutants produce large actin clumps in stationary phase similar to those seen in prk1Delta ark1Delta mutants defective in protein kinases that regulate the actin cytoskeleton. Overexpression of SIW14 in a prk1Delta strain resulted in a loss of cortical actin patches and cables and was lethal. Overexpression of SIW14 also rescued the caffeine sensitivity of the slt2 mutant isolated in the screen, but this was not due to alteration of the phosphorylation state of Slt2. These observations suggest that endocytosis and the organization of the actin cytoskeleton are required for the proper response to nutrient limitation. This hypothesis is supported by the observation that rvs161Delta, sla1Delta, sla2Delta, vrp1Delta, ypt51Delta, ypt52Delta, and end3Delta mutations, which disrupt the organization of the actin cytoskeleton and/or reduce endocytosis, have a phenotype similar to that of whi2Delta mutants.