Development of a lead importin-β1 modulator for therapeutic rescue of TDP-43 pathology in ALS

A common feature in most ALS cases is a disruption of the normal function of a protein called TDP-43. This protein is typically found primarily within the nucleus of a cell, where it helps to regulate essential cell processes, but in ALS, it becomes trapped outside in the cytoplasm forming clumps or aggregates. These clumps are theorized to contribute to motor neuron damage and death. Because of this, treatments aimed at preventing or clearing TDP‑43 clumps could offer a powerful way to slow or stop ALS progression.

Previous research in the lab of Dr. Janice Robertson has identified a small molecule, called JRMS, that strengthens the activity of a protein called importin-β1 (Kpnβ1). This protein acts like a cellular chaperone, helping prevent TDP-43 from misfolding and forming clumps, and assisting in its movement back to the nucleus, where it has important functions. In studies using cells and mouse models, JRMS showed that it could prevent new clumps from forming and help dissolve existing ones, also restoring nuclear TDP-43.

In this project, Dr. Robertson and team will refine and improve JRMS to make it more drug‑like, easier to deliver, and able to reach the brain when taken orally. They will also test its effectiveness in relevant disease models in the lab. If the acquired data shows promising results, the team will also work to prepare the drug for a path to testing in clinical trials. This work represents an important early step toward creating a therapy that directly targets the most common form of ALS pathology, with the long term goal of slowing disease progression.

In 2006, the landmark discovery that 97% of ALS cases had abnormalities in the biology of a protein called TDP-43, shifted fundamental ALS research significantly. Since this, ALS researchers across the globe have been working tirelessly to understand how TDP‑43 becomes disrupted and how to restore its normal function. ALS Canada funding has significantly impacted the field’s continually evolving understanding of this complex system and RNA biology.