Violeta Yu: “TDP-43 aberrant condensates are a therapeutic target shared by 97% of ALS patients”

[Transcript]

TDP-43 is a protein that performs its normal functions in the nucleus. In ALS, it is mostly localized to the cytoplasm and sequestered in cytoplasmic condensates, and this drives the disease through a loss of function in the nucleus as well as toxic gain of function in the cytoplasm, because TDP-43 is in there for too long. This aspect of abnormal condensate biology, mislocalization or sequestration of a component in a condensate is seen in many diseases.

By taking a non-traditional approach to target the condensates in motor neurons, Dewpoint discovered condensate modulators, c-mods, that correct pathological markers of ALS in disease relevant models. So they reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, and reduce neurodegeneration in cells as well as in mouse models. And c-mods targeting the TDP-43 condensatopathy are the first small molecules to potentially address the underlying pathology seen in nearly all cases of ALS.

Condensates offer a common node downstream of all the different causes of ALS. It’s just very difficult to choose a single target upstream of TDP-43 and TDP-43 itself is a difficult protein to drug directly. But by modeling TDP-43 condensates in motor neurons to recapitulate that complexity, that is what has really enabled us to discover drugs that work.