Rationale for the Use of Basimglurant, a Novel mGluR5 Negative Allosteric Modulator, as a Treatment for Seizures Associated with Tuberous Sclerosis Complex
Abstract number :
2.248
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2023
Submission ID :
715
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Delphine Bernard, PhD – Noema Pharma
George Garibaldi, MD – Noema Pharma; Rachel Gurrell, PhD – Noema Pharma
Rationale: Mounting evidence indicate that overactivation of metabotropic glutamate receptor type 5 (mGluR5) is involved in several central nervous diseases, in particular tuberous sclerosis complex (TSC). The present work aimed at understanding the potential utility of basimglurant, a novel mGluR5 negative allosteric modulator (NAM), in the treatment of seizures associated with TSC.
Methods: A literature review was conducted to characterize the relationship between mGluR5 and the pathophysiology of seizures associated with TSC, and to compare basimglurant to other mGluR5 NAMs.
Results: Mutations in TSC genes lead to the formation of benign brain tumours through overactivation of mTOR signalling and to excitatory neuronal imbalance causing seizures. This is associated with overexpression of mGluR5 in TSC brain tumours. Beneficial effects of mGluR5 NAM on seizure phenotypes were observed in two different mouse models of TSC (Kelly E et al. Neuropsychopharmacology 2019;43:1457-1465; Potter W et al. PLoS Biol 2013;11:e1001627). In addition, in vitro studies showed that inhibition of mGluR5 with NAM could reduce the increased rate of protein synthesis. Among mGluR5 NAMs, basimglurant is a highly potent (Kd=1.1 nM for human mGluR5) and selective compound ( > 1,000-fold lower activity at >100 targets including other mGluRs) (Lindemann L et al. JPET 2015; 353:213-33), and it is closely related (chemically and pharmacologically) to the NAM used to demonstrate ‘proof-of-principle’ in a translationally-relevant TSC model.
Conclusions: Taken together, these data suggest a significant role for mGluR5 in pathophysiological mechanisms of TSC. The results from exploratory studies in mouse models of TSC demonstrates proof-of-principle that selective mGluR5 NAMs such as basimglurant could have therapeutic utility on TSC through two parallel mechanisms: 1) normalization of the excitatory neuronal imbalance thereby reducing seizure phenotypes and 2) reduction of protein synthesis in brain cells which may have an impact on tumour growth.
Funding: This study was funded by Noema Pharma and Roche.
Anti-seizure Medications