RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease
- 1University Laval
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.
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BibTeX
@misc{hadjaissa2026raptortargeted,
title = {{RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease}},
author = {I. Hadj-Aissa and M. Muller and A. Desmeules and L. Marcadet and T. Lachance-Brulotte and N. Morin and M.-E. Huot and J. Soliz and C. F. Sephton and P. A. Dutchak},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755052},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755052v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease
AU - I. Hadj-Aissa
AU - M. Muller
AU - A. Desmeules
AU - L. Marcadet
AU - T. Lachance-Brulotte
AU - N. Morin
AU - M.-E. Huot
AU - J. Soliz
AU - C. F. Sephton
AU - P. A. Dutchak
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755052
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755052v1
AB - 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.
ER -