| Title: |
Seizure reduction in TSC2‐mutant mouse model by an mTOR catalytic inhibitor |
| Authors: |
Dhamne, Sameer C.; Modi, Meera E.; Gray, Audrey; Bonazzi, Simone; Craig, Lucas; Bainbridge, Elizabeth; Lalani, Lahin; Super, Chloe E.; Schaeffer, Samantha; Capre, Ketthsy; Lubicka, Danuta; Liang, Guiqing; Burdette, Doug; McTighe, Stephanie M.; Gurnani, Sarika; Vermudez, Sheryl Anne D.; Curtis, Daniel; Wilson, Christopher J.; Hameed, Mustafa Q.; D'Amore, Angelica; Rotenberg, Alexander; Sahin, Mustafa |
| Contributors: |
National Institutes of Health |
| Source: |
Annals of Clinical and Translational Neurology ; volume 10, issue 10, page 1790-1801 ; ISSN 2328-9503 2328-9503 |
| Publisher Information: |
Wiley |
| Publication Year: |
2023 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Objective Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal‐dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy. Methods In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain‐penetrant compared with other mTOR inhibitors. Using a well‐characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1. Results Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development. Interpretation Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/acn3.51868 |
| Availability: |
https://doi.org/10.1002/acn3.51868; https://onlinelibrary.wiley.com/doi/pdf/10.1002/acn3.51868 |
| Rights: |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.DF045151 |
| Database: |
BASE |