ALS pathology and NRG5051 disease-modifying MOA

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons resulting in mortality within an average of 2-5 years from diagnosis. Despite recent success in treating patients with a rare SOD-1 genetic form of ALS, the majority (90%) of patients with sporadic disease remain poorly treated by existing medicines.

The role of toxic TDP-43 aggregates in disease progression

TDP-43 is an essential DNA/RNA-binding protein normally found in the cell nucleus. In ALS, TDP-43 mis-localizes to the cytoplasm, forming toxic, mis-folded aggregates that drive disease progression. In ALS, this TDP-43 ‘gain-of-function’ toxicity, whereby misfolded TDP-43 induces mPTP opening, results in:

  • Mitochondrial DNA (mtDNA) being released into the cytoplasm which stimulates the cGAS/STING innate immune sensor resulting in interferon signaling and downstream neuroinflammation. 1
  • Following mPTP opening and collapse of the mitochondria, the release of cell death factors e.g. cytochrome C are released which contribute to motor neuron cell death.

TDP-43, is the most validated example of a pathogenic protein that activates or sensitizes the permeability transition pore and TDP-43 proteinopathy is found in 97% of ALS cases

90 %

sporadic (sALS)

10 %

familial (fALS)

NRG5051 ALS preclinical studies

In TDP-43 driven preclinical ALS models, NRG5051 inhibited cGAS/STING-induced innate immune gene expression, improved motor function and reduced neuronal cell death.

These data, combined with a profound reduction of the translatable biomarker of neuronal damage, neurofilament light chain (NfL), support NRG5051’s advancement into human clinical trials as a potential ALS treatment.

References

  1. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS: Yu et al., 2020, Cell 183, 636–649