Use of hif-1¿ stabilizing agents for the treatment of type i interferonopathies

Type I interferonopathies represent a subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA- sensing pathways. Among them, Aicardi-Goutières syndrome (AGS) ischaracterised by both neurological and extra-neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. The inventors analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing mutations in three AGS-causing genes, i.e., SAMHD1, RNASEH2B or ADAR1 genes. Using machine-learning approaches and differential gene expression performed on these single-cell data, they identified a drastic loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells of patients. Chemical stabilization of HIF-1α, with a synthetic drug (DMOG) in an in vitro model of AGS, allowed the inventors to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. The inventors therefore propose that inappropriate energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.

Keywords: Type I interferonopathy, Aicardi-Goutières syndrome,HIF-1α
Patent Application number: European Procedure (Patents) (EPA) - 06 Févr. 2023 - 23 305 153.1
Inventors:
MENAGER Mickaël,BATIGNES Maxime

Reference:

BIO23003-T1

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