Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling

Area of Science:

• Genetics and Immunology
• Stem Cell Biology
• Drug Discovery

Background:

• Type I interferonopathies are genetic disorders characterized by systemic inflammation and neurological issues due to upregulated type I interferon (IFN) signaling.
• Current therapeutic options for type I interferonopathies are limited, necessitating the development of novel treatment strategies.
• Induced pluripotent stem cells (iPSCs) offer a promising platform for modeling rare genetic diseases and investigating potential therapies.

Purpose of the Study:

• To develop a strategy for identifying new therapeutic targets for type I interferonopathy using iPSC-based disease modeling.
• To investigate the role of mitochondrial metabolism and specific genes in the pathogenesis of type I interferonopathy.
• To screen for potential drug candidates that can inhibit excessive type I IFN secretion.

Main Methods:

• Genome editing was used to introduce the IFIH1 R779H variant into iPSCs.
• RNA sequencing of iPSC-derived dendritic cells (DCs) identified differentially expressed genes (DEGs).
• Analysis of IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) was performed in iPSC-derived DCs.
• In silico compound screening targeted the OAS-like domain of human OASL, followed by in vitro validation of candidate compounds.

Main Results:

• Transcriptome analysis revealed upregulation of IFN-related and metabolic pathways in IFIH1 R779H-mutated iPSC-derived DCs.
• Increased mitochondrial OCR and ROS generation were observed, and blocking mitochondrial metabolism significantly reduced IFN-α secretion.
• PML was identified as a DEG; arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion.
• In silico predictions identified bisantrene, phthalylsulfathiazole, and ganaplacide as potential inhibitors of IFN-α secretion by binding to the OASL domain.

Conclusions:

• iPSC-based disease modeling is a robust platform for studying type I interferonopathies.
• Targeting mitochondrial metabolism and PML (e.g., with ATO) are potential therapeutic strategies for type I interferonopathy.
• The identified compounds (bisantrene, phthalylsulfathiazole, ganaplacide) show promise for inhibiting excessive IFN-α secretion.