Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease

ALS is 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.

ALS and 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.

The mPTP opening is linked to the pathophysiology in ALS

In ALS, cytoplasmic misfolded TDP-43 induces mPTP opening. This toxic ‘gain-of-function’ 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.
  • Our lead clinical asset, NRG5051 is a potent inhibitor of the mPTP, acting via a novel NLRX1-mediated mechanism-of-action, that protects mitochondrial function and prevents neuronal death.

TDP-43, is the most validated example of a pathogenic protein that activates or sensitizes the mitochondrial permeability transition 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), supported 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