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.

Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.

Diabetic retinopathy (DR) is the commonest cause of blindness in the working-age population of the developed world. The molecular pathophysiology of DR is complex, and a complete spatiotemporal model of the disease is still being elucidated. Recently, a role for angiopoietin (Ang) proteins in the pathophysiology of DR has been proposed by several research groups, and several aspects of Ang signalling are being explored as novel therapeutic strategies. Here, we review the role of the Ang proteins in two important forms of DR, diabetic macular oedema and proliferative diabetic retinopathy. The function of the Ang proteins in regulating blood vessel permeability and neovascularisation is discussed, and we also evaluate recent preclinical and clinical studies highlighting the potential benefits of modulating Ang signalling as a treatment for DR.