Small Molecule Targeting of Chaperone {IP Protein} Prevents and Reverses TDP‐43 Aggregation In‐vitro and In‐vivo

BACKGROUND: Nuclear depletion and neuronal cytoplasmic aggregation of the transactive response DNA-binding protein 43 (TDP-43) is observed in up to 95% amyotrophic lateral sclerosis (ALS) cases, 70% of Alzheimer's Disease (AD) cases, and 50% of frontotemporal dementia (FTD) cases. The cytoplasmic aggregation of TDP-43 has been correlated with inducing neuronal loss. As such, preventing TDP-43 aggregation could have therapeutic potential for ALS/FTD and associated diseases. It has been shown that aggregation of TDP-43 can be attenuated by chaperone proteins. Herein, we have identificatied and validated a new small molecule 'JRMS' as potent binder of {IP-protein} which upregulates its non-canonical chaperone function to prevent/reverse TDP-43 aggregation. METHOD: We developed high throughput models of TDP-43 aggregation by expressing the highly aggregation prone C-terminal fragment TDP-25 in cells through transient expression, mouse primary cortical neurons through lentiviral expression, and organotypic slices and mouse model through AAV9 expression. RESULT: Acute and chronic treatment of JRMS reduced TDP-25 aggregation in a dose-dependent manner by ∼75% in cells. This reduction of TDP-25 aggregates was validated to be dependent on {IP-protein}, and that JRMS elevates activity of the target {IP-protein}. Similarly, in mouse primary cortical neurons transduced with TDP-25 lentivirus, JRMS reduced TDP-25 aggregates by ∼50% reduction. We screened JRMS on organotypic slices from 10 day-old mice inoculated with AAV9-TDP-25. Over 7-days, DMSO treated slices showed ∼60% increase, while JRMS treatment showed a ∼20% reduction in number of TDP-25 aggregates observed prior to treatment. Finally, two weeks treatments of AAV9-TDP-25 expressing mice at 6 weeks of age with JRMS exhibited ∼30% reduction in number of aggregates compared to DMSO control. CONCLUSION: We have validated JRMS as a preclinical therapeutic candidate for the treatment of TDP-43 proteinopathy, with additional preliminary evidence for Tauopathies as well. We are currently working on building a Target Product Profile (TPP) with the goal of providing a drug(s) for clinical testing.

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