Design of an Orally Bioavailable Small Molecule That Modulates the Microtubule-Associated Protein Tau's Pre-mRNA...

Area of Science:

• Neuroscience
• Molecular Biology
• Drug Discovery

Background:

• Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is associated with aberrant splicing of the MAPT gene, leading to toxic 4R tau protein accumulation.
• Current therapeutic strategies for FTDP-17 are limited, highlighting the need for novel treatment approaches targeting the underlying molecular mechanisms.

Purpose of the Study:

• To design and characterize an RNA-targeted small molecule capable of modulating MAPT pre-mRNA splicing.
• To reduce the inclusion of exon 10 in MAPT pre-mRNA, thereby decreasing the production of toxic 4R tau protein.
• To evaluate the therapeutic potential of the designed molecule in cellular and animal models of FTDP-17.

Main Methods:

• Structure-guided drug design was employed to create small molecules targeting a specific regulatory element in the MAPT pre-mRNA.
• In vitro and cellular assays were used to confirm compound binding to the RNA target and assess its effect on pre-mRNA splicing.
• In vivo studies involved oral administration of the compound to a human tau (htau) knock-in mouse model to evaluate its efficacy and pharmacokinetic properties.

Main Results:

• The designed small molecule demonstrated specific binding to the target RNA structure and effectively reduced exon 10 inclusion in various cellular models, including primary neurons.
• Oral administration of the compound in htau mice led to decreased 4R tau protein levels, mitigated cellular pathologies, and improved behavioral deficits.
• The compound exhibited oral bioavailability and blood-brain barrier penetrance, suggesting its potential for treating neurological disorders.

Conclusions:

• This study presents a novel RNA-targeted small molecule that successfully modulates aberrant tau splicing, offering a potential therapeutic strategy for FTDP-17.
• The findings demonstrate a viable pipeline for designing RNA-targeting compounds with oral bioavailability and CNS penetration for treating neurodegenerative diseases.
• The developed molecule effectively reduced toxic tau species and ameliorated disease phenotypes in a relevant animal model, paving the way for further clinical development.