RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease
Hadj-Aissa, I.; Muller, M.; Desmeules, A.; Marcadet, L.; Lachance-Brulotte, T.; Morin, N.; Huot, M.-E.; Soliz, J.; Sephton, C. F.; Dutchak, P. A.
Show abstract
Loss-of-function mutations in the GATOR1 complex (NPRL2, NPRL3, and DEPDC5) are among the most common genetic causes of epilepsy. These mutations impair amino acid-dependent regulation of mTORC1 and cause hyperactive signaling, neuronal hyperexcitability, astrocytic metabolic remodeling, seizures, and early mortality. Here, we report the development of antisense oligonucleotides (ASOs) targeting RAPTOR, an mTORC1 scaffolding subunit, to correct pathological mTORC1 hyperactivity caused by defective upstream regulation. RAPTOR-targeted ASO treatment reduced RAPTOR expression in mouse and human systems and dampened mTORC1 signaling in GATOR1-deficient models. ASO-mediated RAPTOR reduction rescued neuronal hyperexcitability, corrected astrocytic mitochondrial dysfunction, and suppressed spontaneous seizures in vivo. A single treatment significantly extended longevity across neuronal and astrocytic models of GATOR1 deficiency. Collectively, these findings establish RAPTOR-targeted ASOs as a mechanism-based therapeutic approach that durably corrects cellular and circuit-level consequences of GATOR1 deficiency. By tuning RAPTOR abundance, this strategy provides a therapeutic framework for mTORC1-driven epilepsies and related diseases.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy 93%
- Reducing methylation of histone 3.3 lysine 4 in the medial ganglionic eminence and hypothalamus recapitulates neurodevelopmental disorder phenotypes 92%
- Pathogenic variants in autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation 92%
Similar papers in this journal
- Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs 93%
- Optogenetic stimulation of dorsal striatum bidirectionally controls seizures 92%
- S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.