Abstract
Purpose :
Inherited Retinal Degeneration (IRD) causing mutations have time-dependent impact directing degeneration of target cells and progressive vision loss. Identification and molecular characterization of the thousands of mutations in the ~300 currently identified IRD genes is an arduous challenge, and a deterrent for diagnoses and treatment. We hypothesize that disease-gene adjacent processes – that operate to restore homeostasis – can be gene-agnostic targets for therapeutic interventions. We employ a multi-omics network medicine study for comprehensively detecting these cellular processes to assemble a retinal diseasome – a unified network capturing associations among retinal disease genes, auxiliary pathways, and molecular signatures that together represent the dynamic events preceding degeneration of retinal cells.
Methods :
Transcriptomes from purified rod photoreceptors from rd1, rd16, rd10, rds, Aipl1-/- and Rpgrip1-/- mice between postnatal day (P)2 through P10 have been generated. These mutants represent a series of disease genes that function distinctly in rod photoreceptors. We compared time-series mutant transcriptomes with wildtype to identify gene modules active in pre-disease stages. Disease modules will be bioinformatically integrated into a diseasome network.
Results :
Our data shows significant alterations as early as P2 and P4 in rod transcriptomes from multiple mutants, with progressive dysregulation with passing time. This observation suggests that disease-linked adaptation begin significantly earlier in rod photoreceptors. Co-expression analyses spotted groups of genes trending together. Interestingly, mutant transcriptomes had overlapping as well as unique trends. Gene modules of energy metabolism and autophagy were found in multiple mutants including rd1 and rd16, whereas fatty acid metabolism was selectively perturbed in rd16 rods. Interesting time-dependent drifts were observed in specific metabolic and signaling pathways such as one-carbon metabolism. Assembling gene modules into a pan-IRD diseasome will be helpful in identifying leads for gene-agnostic treatments.
Conclusions :
A retinal diseasome will inform mechanisms of rod degeneration in IRD. Shared auxiliary gene modules offer attractive candidates for developing therapies for multiple pathologies. Similar approach can be extended to other pathologies such as age-related retinal disorders.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.