Targeting the muscarinic M1 receptor with a selective, brain- penetrant antagonist to promote remyelination in multiple sclerosis (Publication with Expression of Concern. See vol. 122, 2025)

• 成果类型: Article; Publication with Expression of Concern
• 署名作者: Poon, Michael M.; Lorrain, Kym I.; Stebbins, Karin J.; Edu, Geraldine C.; Broadhead, Alexander R.; Lorenzana, Ariana J.; Roppe, Jeffrey R.; Baccei, Jill M.; Baccei, Christopher S.; Chen, Austin C.; Green, Ari J.; Lorrain, Daniel S.; Chan, Jonah R.
• 署名单位: University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10897
• DOI: 10.1073/pnas.2407974121
• 发表日期: 2024-08-06
• 关键词: acetylcholine-receptor; differentiation; protein; identification; demyelination; myelination; pathology; m1-toxin; lesions; cells

摘要

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE- 307, a brain- penetrant, small- molecule antagonist with favorable drug- like properties that selectively targets M1R. We evaluate PIPE- 307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2- 5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE- 307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE- 307 for clinical studies.