Age-related macular degeneration study finds causative genes, disproves assumptions 2023

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In Cell Genomics, Genentech’s South San Francisco research unit found therapeutic candidates for age-related macular degeneration (AMD), which affects 200 million people globally. AMD blinds.

In “A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration,” the researchers describe how they used a molecular atlas of AMD pathology progression phases to discover genes targetable by treatment.

23 significant genome-wide regions were differently methylation in AMD. AMD-affected eyes had over 1,000 differently expressed genes. The study identifies AMD-related gene upregulations and hereditary risks.

To investigate AMD molecular alterations, researchers collected bulk-tissue and single-cell transcriptomics and epigenomics data from 85 distinct human donor eyes. Early, intermediate, and two advanced-stage AMD tissue transcriptomes were examined.

AMD and control donors revealed no genome-wide alterations.

The study’s Müller glia cell clusters—basal, AMD, and gliotic—are intriguing. The basal Müller cluster was 62% control and 80% AMD donor. Although Müller gliosis is widespread in retinal disorders and damage, the AMD Müller cluster did not express gliosis markers (upregulated glial fibrillary acidic protein). This observation in real-world disease conditions differs from retinal damage models employed in AMD translational research.

The findings also suggests that the gliotic state is a key intermediary between normal Müller glia and stem cell identity in retinal regeneration. This shows that when retinal regeneration research translates into treatment options, a deeper understanding of the disease state Müller glia is essential, as medicines designed to reprogram the basal or gliotic Müller may not work for AMD-like states.

In contrast to 2018 John Hopkins research, “ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration,” published in Nature Communications, the Genentech researchers found no global reduction in open chromatin.

AMD and control samples had the same cell types and subtypes.

Based on prior findings, the current investigation expected to observe disease-related chromatin accessibility abnormalities with greater detail.

However, the current study did not replicate the previous research findings of a shift in chromatin accessibility either globally or at specific loci, suggesting that cell death in the sample and nuclei from non-disease-related cell types confounded the bulk analysis.

The Genentech researchers, along with colleagues from the University of Utah and the State University of New York at Buffalo, have dispelled some past assumptions and confounding research attempts and identified a robust number of relevant gene mechanisms related to AMD that will likely form the basis for future research.

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