ACE-2223

Targeting TDP-43 to treat amyotrophic lateral sclerosis (ALS)

TDP-43 is the most critical regulator of the cascade of reactions that leads to ALS

TDP-43 is a vital protein involved in a wide range of cellular activities, most notably including regulation of mRNA splicing. It is involved in many neurodegenerative diseases and is the most critical regulator of the cascade of inflammatory reactions that leads to ALS. This cascade contributes to ongoing cellular stress and eventually the death of motor neurons.

For those living with ALS, the loss of motor neurons gradually limits muscle control, eventually leading to the inability to swallow and breathe. There are approximately 30,000 people living with ALS in the United States, and the average lifespan after diagnosis is 2-5 years. There are no approved therapies that address the cause of the disease or significantly slow its progression.

ACE-2223 is a small molecule designed to specifically target misfolded TDP-43 that leads to disease pathology.

In ALS, TDP-43 accumulates as large inclusions or aggregates in the cytoplasm via a toxic hexameric intermediate. These misfolded aggregated forms lead to a loss of TDP-43 function normally carried out by monomeric and dimeric forms in the nucleus. The lack of healthy TDP-43 leads to a breakdown of mRNA function, resulting in a range of incorrect or missing proteins throughout the cell.

The complexity of misfolded TDP-43 has historically made its structure hard to analyze. It has also rendered difficult the design of drugs that directly target it – until our work at Acelot.

Mass removal of TDP-43 from neurons leads to cellular death. By contrast, an ideal drug mechanism disrupts the disease-associated form of TDP-43, thus shifting the equilibrium back to the healthy form of TDP-43. This functional TDP-43 can then appropriately regulate mRNA splicing and correct translation of a wide range of proteins.

ACE-2223: Our solution to restore the healthy form and function of TDP-43

Click above for a snapshot of the biology involved

Data supporting ACE-2223

    • Highly blood-brain-barrier (BBB) permeable

    • Reduces pathological TDP-43

    • Rescues neuroinflammation

    • Reduces neurofilament-light chain

    • Improves survival and motor function

    • Inhibits TDP-43 aggregation

    • Dissociates preformed TDP-43 aggregates

    • Rescues mRNA mis-splicing

    • Rescues functional TDP-43

    • Increases neuronal survival

    • Improves synaptic defects