Development of peptide-oligonucleotide conjugates to target poly (ADP-ribose) polymerase for new RNA-based amyotrophic lateral sclerosis therapy

Amyotrophic lateral sclerosis (ALS) is an incurable disease of motor neuron degeneration in the brain and spinal cord, leading to paralysis of voluntary muscles and death by respiratory failure within a median of 3 years from onset.

The exact cause of amyotrophic lateral sclerosis (ALS) is largely unknown. However, mutant genes have been identified that contribute to 5-10% of ALS cases. In more than 90% of ALS patients, an RNA/DNA-binding protein, TDP-43, which is ordinarily present in nuclear, redistributes to the cytoplasm and forms aggregates. This eventually leads to the degeneration of motor neurons. A recent study (1) has shown that the elevated activity of poly (ADP-ribose) polymerase (PARP) in the nucleus contributes to the formation of cytoplasmic TDP-43 aggregates. Therefore, lowering the level of PARP can mitigate the formation of cytoplasmic TDP-43 aggregates and prevent motor neuron degeneration.