RESUMO
The complement system is crucial for immune surveillance, providing the body's first line of defence against pathogens. However, an imbalance in its regulators can lead to inappropriate overactivation, resulting in diseases such as age-related macular degeneration (AMD), a leading cause of irreversible blindness globally affecting around 200 million people. Complement activation in AMD is believed to begin in the choriocapillaris, but it also plays a critical role in the subretinal and retinal pigment epithelium (RPE) spaces. Bruch's membrane (BrM) acts as a barrier between the retina/RPE and choroid, hindering complement protein diffusion. This impediment increases with age and AMD, leading to compartmentalisation of complement activation. In this review, we comprehensively examine the structure and function of BrM, including its age-related changes visible through in vivo imaging, and the consequences of complement dysfunction on AMD pathogenesis. We also explore the potential and limitations of various delivery routes (systemic, intravitreal, subretinal, and suprachoroidal) for safe and effective delivery of conventional and gene therapy-based complement inhibitors to treat AMD. Further research is needed to understand the diffusion of complement proteins across BrM and optimise therapeutic delivery to the retina.
RESUMO
Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the developed world. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlying retinal pigment epithelium (RPE) and choroidal endothelial cells. The molecular events that underline the development of these cell types from in utero to adult as well as the progression to intermediate and advanced stages AMD are not yet fully understood. We performed single-cell RNA-sequencing (RNA-Seq) of human fetal and adult RPE-choroidal tissues, profiling in detail all the cell types and elucidating cell type-specific proliferation, differentiation and immunomodulation events that occur up to midgestation. Our data demonstrate that progression from the fetal to adult state is characterized by an increase in expression of genes involved in the oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE-choroid tissue. Single-cell comparative transcriptional analysis between a patient with intermediate AMD and an unaffected subject revealed a reduction in the number of RPE cells and melanocytes in the macular region of the AMD patient. Together these findings may suggest a macular loss of RPE cells and melanocytes in the AMD patients, but given the complex processing of tissues required for single-cell RNA-Seq that is prone to technical artefacts, these findings need to be validated by additional techniques in a larger number of AMD patients and controls.
