Scientists Discover How to Prevent Death of Nerve Cells in Most Common Genetic Forms of MND and Dementia

By University of Sheffield

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

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

The Sheffield team previously discovered the abnormal transportation of the rogue RNAs copied from the C9ORF72 gene—known to be the most frequent cause of MND and FTD—is caused by excessive stickiness of a cell transporter named SRSF1.

Instead of using conventional drugs, which are inefficient in disrupting the stickiness of the SRSF1 protein, or invasive therapies to edit or modulate the activity of defective genes, the new study found that a small peptide incorporating a cell-penetrating module can stick to SRSF1 and effectively block the transportation of the rogue repeat RNA.

The peptide is composed of a short chain of amino acids or bricks found within our cells and tissues in the body.

Interestingly, the findings, published in the journal Science Translational Medicine also suggest the peptide could be given to MND and FTD patients orally in a non-invasive manner—for example through a nasal spray which could be developed to enter the brain.

This groundbreaking concept of using peptides to block the effects of the damaging repeat expanded RNA and toxic repeat proteins could transform how some neurodegenerative conditions which 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 food eaten by fruit flies not only did the peptides block the damaging mutations which cause MND and FTD from being transported to the cell's nucleus, we actually saw an improvement in their 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.

"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."

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 aged 45–65 and can affect behavior, personality, language and movement. There is no cure for FTD, and no treatments available to slow or stop the progression of the disease.

MND is a debilitating condition that destroys the cells that control movement, leaving sufferers unable to move, walk, talk and eventually breathe. Treatments are very limited and there is no cure. Most patients with the disease are only expected to live two to five years after diagnosis. This study was made possible thanks to donated tissue samples from the skin of MND patients which 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 in support of a completely new strategy to treat the most common inherited cause of both MND and FTD, with the ultimate goal of developing effective therapies for these devastating diseases."

Significant CMS Prior Authorization Changes on the Horizon: Your Voice Needed

APTA

Don't miss this chance for the profession to make headway in reducing administrative burden.

When it comes to the U.S. Centers for Medicare & Medicaid Services, chances to effect significant change don't come around that often — and when they do, opportunities shouldn't be passed up. That's precisely the scenario the physical therapy profession now faces in a crucial area in need of reform: prior authorization. APTA is urging members and supporters to make their voices heard before a looming March 13 deadline.

"A Real Difference for Providers"
In three separate proposed rules, CMS lays out significant changes to prior authorization practices across a broad range of programs including Medicare Advantage, state Medicaid and Children's Health Insurance Program fee-for-service plans, Medicaid managed care plans, CHIP managed care entities, and Qualified Health Plan issuers in the federal ACA insurance exchanges. The trio's headliner is a sweeping provision that would significantly increase transparency and streamline the prior authorization process, while related but smaller-scale rules would address current inconsistencies around how data is exchanged and establish clinician advisory committees to inform utilization management in Medicare Advantage organizations.

Provider concern over the administrative burden associated with prior authorization isn't new, and reining in its misuse has been a constant feature of APTA's advocacy efforts. Over the years, CMS has acknowledged that the issue needs to be addressed, but this is the closest the agency has come to taking action (CMS proposed reforms to prior authorization in 2020 but never acted on them).

"It's difficult to overstate the importance of these proposed rules, particularly the large-scale rule that affects multiple programs," said Kate Gilliard, APTA's director of health policy and payment. "While it's true the proposals won't completely eliminate prior authorization, CMS is offering up changes that will make a real difference for providers — particularly PTs, who are typically saddled with more prior authorization than the average clinician. That's why it's so important that the profession seize this critical opportunity and make its voice heard."

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