Researchers at the University of Sheffield have discovered how to prevent the production of toxic repeat proteins that cause the death of nerve cells in neurodegenerative diseases like FTD and ALS.

The study was centered specifically around FTD caused by a mutation in the C9orf72 gene, FTD’s most common genetic cause. In most people, the C9 segment repeats up to approximately 24 times. But in persons with FTD caused by this mutation, the segment is repeated over 60 times, which can lead to the abnormal accumulation of toxic nerve-cell-harming proteins.

In a study published in the journal Science Translational Medicine, the research team at Sheffield says that it is possible to halt the accumulation of these toxic proteins by blocking the transportation of mutated RNA segments that trigger the production of the proteins.

The study authors used a cell-penetrating peptide, a small bundle of amino acids (the building blocks of proteins), to stop the movement of the mutated RNA from the cell nucleus (the core that regulates cellular activity and holds genetic information) to the cytoplasm (the liquid within a cell’s membrane around the nucleus where many cellular functions occur, including protein production). Blocking this movement was accomplished by targeting a protein involved in the transportation of RNA, called SRSF1. When the cell-penetrating peptide sticks to SRSF1, the protein is blocked from carrying the mutated RNA.

“Keeping these repeat transcripts in the nucleus so they can’t exit into the cytoplasm prevents them from making the neurotoxic repeat proteins involved in ALS and FTD,” senior study author Guillaume Hautbergue, PhD, told Neurology Today. “These [proteins] are one of the main drivers of these diseases.”

A similar approach was used in Wave Life Sciences’ FOCUS-C9 clinical trial evaluating the drug WVE-004, which targeted the protein poly(GP). The trial ended in May 2023, with the company finding there was no clinical benefit for participants with FTD or ALS. Despite the results of the trial, Wave Life Sciences proved not only the worth of biomarkers, but also the viability of using them as drug targets; poly(GP) levels were reduced in participants, indicating that the drug had reached its target. Additionally, as the results of the University of Sheffield’s study show, there are still other biomarkers with potential to be drug targets.

Tests of the cell-penetrating peptide were carried out using various models, including cell cultures, lab flies and mice, and neuronal cells grown from progenitor cells from persons with a C9 mutation. For comparison, the researchers also tested the peptide on neuronal cells from progenitor cells donated by persons without FTD or an FTD-causing mutation. In all the models, the peptide successfully kept the mutated RNA in the nucleus of cells, preventing it from entering the cytoplasm to spark toxic protein production.

The authors noted that the peptide could be administered non-invasively, either ingested orally as a drug or inhaled through a nasal spray that could be specially developed for it.

“This concept of using peptides to block destructive mutations unlocks such an exciting and innovative treatment pathway,” Dr. Hautbergue said. “[ALS] 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.”

Researchers have discovered more than a dozen genes that cause FTD, though three specific genes, including C9orf72, cause most genetic FTD cases. Genetic testing can evaluate if you face a risk of genetic FTD – however, AFTD strongly recommends genetic counseling as a first step to consider if genetic testing is right for you.