MyD88 inhibitory gene therapy for RPE degeneration--Yr 2

Recent work in my laboratory identified a new signaling pathway that contributes to retinal pigmented epithelium (RPE) degeneration in atrophic age-related macular degeneration (AMD), involving activation of the adaptor MyD88 as a critical step in cell death (Tarallo et al., Cell 2012). This pathway component is essential in the context of deficiency of the enzyme DICER1 or accumulation of cytotoxic Alu repetitive RNA transcripts that occurs in the RPE of human geographic atrophy eyes (Kaneko et al., Nature 2011). In this proposal, we seek to investigate the utility of MyD88 inhibition via gene therapy in the two animal models of RPE degeneration. This research advances a new framework for treating geographic atrophy and retinal degeneration due to ABCA4 deficiency. These diseases are poorly managed by current therapies. This work builds on recent published findings and preliminary data from my laboratory that identify MyD88 signaling as an attractive therapeutic target. Successful completion of this work will both increase our basic understanding of the importance of MyD88 signaling in ABCA4 diseases, as well as advance a promising therapeutic for human disease. The data generated from these studies will form the foundation of future clinical trials in human patients to address these pressing clinical needs, which aligns well with the Foundation’s stated goals.