Development of peptide-oligonucleotide conjugates to knockdown poly(ADP-ribose) polymerase as a novel RNA-based therapy for amyotrophic lateral sclerosis

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 aim of this project is to use oligonucleotide-based therapeutic approach to knockdown the level of PARP. In this project, two classes of antisense oligonucleotides will be designed and tested for their efficacy in lower the level of PARP protein in NSC-34 (motor neuron-like) cells.

Although the exact cause of ALS is largely unknown, 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 normally present in nuclear, redistributes to the cytoplasm and form 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 contribute 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.


McGurk, L. et al. Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathologica Communications (2018) 6:84

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