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Scientists have found a novel way to block the transport of mutant RNA and the subsequent production of toxic repeat proteins that lead to nerve cell death in the most common MND and FTD subtypes.

Scientists have found a new way to block the transport of mutant RNA and the subsequent production of toxic repeat proteins that lead to nerve cell death in the most common genetic subtypes of motor neuron disease (MND) and frontotemporal dementia ( FTD).

The new study, conducted by researchers at the University of Sheffield’s Institute for Translational Neuroscience (SITraN), also showed that using a peptide to stop the transport of mutant repeat RNA molecules and the production of toxic repeat proteins actually increases the survival of C9ORF72 nerve cells. protecting them against neurodegeneration.

The Sheffield team previously discovered that abnormal transport of the malicious RNAs copied from the C9ORF72 gene, known to be the most frequent cause of MND and FTD, is caused by excessive adherence of a cellular transporter called SRSF1.

Instead of using conventional drugs, which are ineffective at disrupting the adherence of the SRSF1 protein, or invasive therapies to edit or modulate the activity of faulty genes, the new study found that a small peptide incorporating a cell-penetrating module can attach to SRSF1 and effectively block the transport of the rogue repeat RNA.

The peptide is made up of a short chain of amino acids or building blocks found within our cells and tissues in the body.

Interestingly, the findings, published in the journal Science Translational Medicine they also suggest that the peptide could be delivered to MND and FTD patients orally or in another non-invasive way, for example through a nasal spray that could be developed to enter the brain.

This innovative concept of using peptides to block the effects of harmful expanded RNA repeats and toxic repeat proteins could transform the way some neurodegenerative conditions that currently have no cure are treated.

Professor Guillaume Hautbergue, Professor of Translational RNA Biology at the University of Sheffield, who led the study, said: “When we tested our innovative approach by adding the peptide to the foods the fruit flies eat, the peptides not only blocked the harmful mutations that cause MND and FTD to be transported into the cell’s nucleus, we actually saw a improvement in their neurofunction.

“This means that the peptide effectively blocks the progression of the neurodegenerative condition and also helps to restore the function of the affected nerve cells.

“This concept of using peptides to block destructive mutations opens up such an exciting and innovative treatment avenue that has not been explored by scientists until now.

“MND and FTD are devastating diseases that currently have no cure. This is a promising alternative to conventional small molecule drugs that are often limited by poor penetration of the blood-brain barrier.”

FTD occurs when nerve cells in the frontal and temporal lobes of the brain are lost, causing the lobes to shrink. FTD most commonly affects people ages 45 to 65 and can affect behavior, personality, language, and movement. There is no cure for FTD and there are no treatments available to slow or stop the progression of the disease.

MND is a debilitating condition that destroys cells that control movement, leaving patients unable to move, walk, talk, and eventually breathe. Treatments are very limited and there is no cure. Most patients with the disease are expected to live two to five years after diagnosis. This study was made possible by donated tissue samples from the skin of MND patients that were reprogrammed into nerve cells.

Dr. Brian Dickie, Director of Research at the MND Association, said: “These findings from a world-leading research team in Sheffield demonstrate the importance of funding fundamental ‘discovery’ science. This work has provided important evidence supporting an entirely new approach to treat the most common inherited cause of MND and FTD, with the ultimate goal of developing effective therapies for these devastating diseases.”

The innovative research, conducted in collaboration with multiple laboratories at SITraN and with the groups of Dr. Alexander Whitworth (University of Cambridge), Dr. Cyril Domínguez (University of Leicester), Professor Frédéric Allain (ETH Zurich) and funded by the MND The UKRI BBSRC and MRC Association and councils will transform the future of clinical trials for the most common genetic forms of MND and FTD in the coming years.

Notes to editors:

This research was driven by a biomedical grant from the MND Association and further supported by UKRI through the BBSRC and MRC New Investigator research grants.

Media Contact: For more information, please contact: Amy Huxtable, Head of Public Relations and Media, University of Sheffield, 07568116781, [email protected]