The research center of Genentech in South San Francisco conducted a study that focused on finding drug targets for age-related macular degeneration (AMD), a condition affecting the vision of approximately 200 million people worldwide and that can lead to blindness.
The study, titled "A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration," described the researchers' efforts to pinpoint genes that can be targeted through treatment using a molecular atlas of the different stages of AMD pathology development.
The study conducted on AMD led to the discovery of 23 crucial genome-wide loci, which exhibit differential methylation. Moreover, the research found more than 1,000 genes that are differentially expressed in various disease stages and distinct Müller cell states of AMD-affected eyes. The study's outcomes underscore the upregulation of causal genes and genetic risks that underlie AMD.
The researchers collected bulk-tissue and single-cell transcriptomics and epigenomics data from 85 distinct human donor eyes to gain insights into the molecular transformations taking place during the progression of AMD. The tissue transcriptomes of early, intermediate, and two different types of advanced-stage AMD were analyzed in the study.
The study yielded fascinating results on the distinct clusters of Müller glia cell states, which include basal, AMD, and gliotic. Of note, 62% of the basal Müller cluster originated from controls, whereas 80% of the AMD Müller cluster came from AMD donors. Despite Müller gliosis being a typical feature in retinal diseases and injury, the study authors highlight that the AMD Müller cluster did not exhibit increased expression of gliosis markers, such as upregulated glial fibrillary acidic protein. This observation in actual human disease states diverges from retinal injury models commonly employed in AMD translational research.
Furthermore, the study indicates that the gliotic state serves as a significant intermediary between normal Müller glia and stem cell identity in retinal regeneration. This implies that, as research on retinal regeneration progresses into therapeutic strategies, it is crucial to have a thorough comprehension of the disease state of Müller glia. Potential therapeutics that aim to reprogram basal or gliotic Müller cells may not be appropriate for the AMD-like state.
The comparison between control and AMD donors revealed no significant differences at the genome-wide level. Similarly, there were no apparent dissimilarities between the cell type or subtype levels in the control and AMD samples.
Interestingly, the findings of the Genentech study contrast with the earlier research conducted by John Hopkins researchers in 2018, titled "ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration," published in Nature Communications. In this study, the AMD disease state was correlated with a global reduction of open chromatin, which differed from the lack of a corresponding shift in chromatin accessibility found in the Genentech study.
Due to the previously reported observation, the current study anticipated detecting variations in chromatin accessibility associated with the disease state in greater detail. However, contrary to expectations, the current study did not replicate the earlier findings of a shift in chromatin accessibility either globally or at specific loci. This suggests that the changes in chromatin accessibility observed in the previous bulk analysis may have resulted from cell death in the sample, with nuclei from non-disease-related cell types causing confusion.