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.
Our research project aims to use oligonucleotide-based therapeutic approach to knock down the level of polymerase (PARP). In this project, two classes of antisense oligonucleotides will be designed and tested for their efficacy in lowering the polymerase (PARP) protein level in NSC-34 (motor neuron-like) cells.
McGurk, L. et al., 2018. Nuclear poly (ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathologica Communications, 6:84.