Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that currently have no cure. Both diseases commonly involve the transportation of mutant RNA from the nucleus to the cytoplasm, resulting in the production of toxic proteins that induce neuron death. A team led by researchers from the University of Sheffield have developed a new approach for protecting nerve cells from destruction and have designed a novel peptide that prevents the transportation of harmful repeat RNA.
The most common subtypes of ALS and FTD involve repeat expansions in the C9ORF72 gene, which are copied into RNA and transported into the cytoplasm by the cell transporter serine/arginine-rich splicing factor 1 (SRSF1). The small, cell-penetrating peptide designed by the researchers works by attaching to SRSF1, competing with the repeat transcripts and preventing their transportation outside the nucleus. The peptide could be administered orally or through a nasal spray, making it a potential noninvasive treatment.
The research team tested the peptide’s ability to prevent transportation and translation of the mutant RNA transcripts on HEK293T cells, Drosophila and mouse models for ALS and FTD, as well as in neurons differentiated from induced neural progenitor cells (iNPCs) derived from ALS patient tissue samples. The team confirmed that the peptide blocked the nuclear export of mutant RNA in HEK293T cells, as well as prevented the production of harmful dipeptide repeat proteins (DPRs) in the patient-derived cells. Additionally, in the fruit fly models, oral administration of the peptide reduced DPR levels and even improved the motor function of the treated flies. Injecting the peptide into the brains of ALS/FTD model mice reduced the expression of DPRs in the brains, the authors wrote. This research was published in Science Translational Medicine.
“This concept of using peptides to block destructive mutations unlocks such an exciting and innovative treatment pathway which until now has not been explored by scientists,” said Guillaume Hautbergue, professor of translational RNA biology at the University of Sheffield, who led the study. “MND and FTD are devastating diseases which currently have no cure. This is a promising alternative to conventional small molecule drugs which are often limited by poor penetration of the blood-brain barrier.”
The study was conducted in collaboration with researchers from the University of Cambridge, University of Leicester and ETH Zurich. The researchers hope to see this potential treatment move to clinical trials within the next few years.