Drug Development.

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Transactive response DNA-binding protein 43 (TDP-43) aggregation is a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's Disease (AD), and frontotemporal dementia (FTD).
• TDP-43 cytoplasmic aggregation is linked to neuronal loss, making its prevention a key therapeutic target.
• Chaperone proteins can attenuate TDP-43 aggregation, suggesting a potential therapeutic strategy.

Purpose of the Study:

• To identify and validate a novel small molecule, JRMS, that targets TDP-43 aggregation.
• To investigate the mechanism by which JRMS modulates TDP-43 aggregation through {IP-protein} chaperone activity.
• To assess the preclinical efficacy of JRMS in reducing TDP-43 aggregation in various models.

Main Methods:

• High-throughput screening models were developed using cellular expression of TDP-25, a highly aggregation-prone fragment of TDP-43.
• In vivo validation was performed in mouse primary cortical neurons, organotypic slices, and a mouse model using lentiviral and AAV9 delivery systems.
• JRMS treatment efficacy was evaluated by quantifying TDP-25 aggregate reduction in response to varying doses and durations of treatment.

Main Results:

• JRMS demonstrated dose-dependent reduction of TDP-25 aggregation by approximately 75% in cellular models.
• The observed reduction in TDP-25 aggregates was dependent on {IP-protein}, with JRMS enhancing its chaperone activity.
• In vivo studies showed significant reduction in TDP-25 aggregates in mouse neurons (∼50%), organotypic slices (∼20% reduction), and a mouse model (∼30% reduction).

Conclusions:

• JRMS is validated as a preclinical therapeutic candidate for TDP-43 proteinopathies.
• Preliminary evidence suggests potential efficacy for JRMS in treating tauopathies as well.
• Further development is underway to create a Target Product Profile for clinical testing of JRMS.