TDP-43 accumulation is observed as TDP-43 inclusion bodies in diseased neurons of many neurodegenerative disorders (ND), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), hippocampal sclerosis of aging (HS-Aging), chronic traumatic encephalopathy and limbic predominant age-related TDP-43 encephalopathy (LATE). Normally, the TDP-43 protein is highly expressed during early development, but should gradually disappear later in our lives. When re-expressed, it can induce the three hallmarks of neurodegeneration: amyloid plaques, Tau neurofibrillary tangles, and TDP-43 inclusion bodies. Moderate levels of TDP-43 are capable of kill neuron in a few weeks,making it the most toxic protein to adult neurons known so far.
As a critical regulator of the CFTR protein, TDP-43 also plays an important role in cystic fibrosis (CF). High TDP-43 activity not only reduces full-length CFTR protein levels but also keeps the protein from being transported to cell surface where it functions. Inhibiting TDP-43 can increase CFTR or dF508CFTR on cell surface, with great potential of becoming a true CF cure.
The toxicity of TDP-43 comes from its nucleic acid binding activity. Our compounds remove it by specifically blocking this activity.