Researchers have designed a peptide that can block the toxic effects of a protein linked with neurodegenerative disease, which could potentially be delivered via nasal spray.
The peptide was able to prevent the death of nerve cells and protect them from degeneration in animal models of amyotrophic lateral sclerosis (ALS)—the most common form of motor neurone disease (MND)—and frontotemporal dementia (FTD).
The cell-permeable peptide stops the damage caused from mutant repeated protein transcripts by blocking their transportation out of the cell’s nucleus.
This prevents them from entering the cytoplasm where they can produce toxic repeat proteins that lead to nerve cell death, the team explains in Science Translational Medicine.
Study lead Guillaume Hautbergue, a professor of translational RNA biology at the University of Sheffield, U.K., said that putting the peptide into food eaten by fruit flies halted the transport of damaging mutations and also improved the insects’ neurofunction.
“This means the peptide is effectively blocking the progression of the neurodegenerative condition and also helping to restore the function to the affected nerve cells,” he explained.
“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.
“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.”
ALS and FTD usually manifest in adulthood and can lead to muscle weakness, paralysis and both cognitive and personality changes.
They are often connected to hexanucleotide repeat expansions in the C9ORF72 gene. Translation of these repeat transcripts leads to the production of toxic dipeptide repeat proteins (DPRs) that can cause neurodegeneration.
The researchers developed a peptide called WT-CPP that could prevent pathological C9ORF72 repeat RNAS from exiting the nucleus, thereby inhibiting the production of the DPRs in flies and mice.
WT-CPP also prevented the translation of toxic DPRs in neurons derived from people with ALS mutations as well as boosting the neurons’ survival.
In addition, oral doses of the peptide slowed the translation of DPRs in a fruit fly model of ALS/FTD and reversed movement deficits.
The peptide was further able to act on the brains of ALS/FTD mice and it reduced DPR expression.
“Our current study further reinforces the concept that the nuclear export of mRNAs can be manipulated therapeutically in neurodegenerative disease models,” the researchers say.