Interleukin-1 receptor-associated kinase 3 (IRAK-M) (IRAK-M)

Interleukin-1 receptor-associated kinase 3 (IRAK-M) is a member of the IRAK family that functions as a critical negative regulator of the Toll-like receptor (TLR) and Interleukin-1 receptor (IL-1R) signaling pathways (UniProt Q9Y616). Unlike other IRAK proteins, IRAK-M is a pseudokinase that lacks catalytic activity; it acts by preventing the dissociation of IRAK1 and IRAK4 from the MyD88 adapter protein, thereby stabilizing the Myddosome complex in an inactive state and inhibiting downstream pro-inflammatory signaling (PubMed: 12150924). In the retinal pigment epithelium (RPE), chronic inflammation and oxidative stress lead to overactivation of the Myddosome, contributing to the pathogenesis of geographic atrophy (GA) and age-related macular degeneration (AMD) (PubMed: 33055214). JNJ-81201887 is an investigational AAV-based gene therapy designed to deliver a modified version of IRAK-M to RPE cells, aiming to restore immune homeostasis and protect the retina from progressive degeneration (ClinicalTrials.gov: NCT04437368). By specifically targeting the Myddosome complex within the RPE, IRAK-M modulation represents a novel approach to treating vision loss by dampening localized innate immune responses.

Other names

IRAK3Interleukin-1 receptor-associated kinase MIRAK-3

Negative regulation of the Myddosome complex to inhibit pro-inflammatory TLR/IL-1R signaling