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

Topic: Brain proteins, microglia and lab models

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. 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.

@article{shenouda2025-41447225,
  author  = {Shenouda, Marc and Robertson, Janice},
  title   = {{Small Molecule Targeting of Chaperone IP Protein Prevents and Reverses TDP‐43 Aggregation In‐vitro and In‐vivo}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70859_099984},
  pmid    = {41447225},
  url     = {https://doi.org/10.1002/alz70859_099984}
}

Key findings

• 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.

Why it matters

A small molecule called JRMS reduced clumps of TDP-25 protein in cells and in mice, including a roughly 30% reduction in aggregates after two weeks of treatment in mice. The authors call JRMS a preclinical candidate and say they are still working toward a product profile before it can be tested in clinical trials.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70859_099984
• PubMed: 41447225
• Original source →
• Free full text: Alzheimer s & Dementia →

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