Gene-silencing tool promises to end deadly brain disorders

Researchers have developed a molecular-editing system capable of penetrating the brain to halt the production of proteins linked to prion diseases, a fatal group of neurodegenerative conditions [1].

This innovative tool, the coupled histone tail for autoinhibition release of methyltransferase (CHARM), modifies the epigenome: chemical tags on DNA that influence gene activity.

In experimental studies with mice, CHARM effectively silenced the gene responsible for these dangerous proteins in most neurons throughout the brain without changing the DNA sequence itself.

According to co-author Madelynn Whittaker, a bioengineer from the University of Pennsylvania, CHARM’s significance lies in its potential to offer a safe and long-lasting solution for diseases caused by protein malfunctions.

Unlike previous methods that required repeated treatments and could cause side effects like liver damage, CHARM’s approach could represent a groundbreaking ‘one-and-done’ treatment.

In fatal familial insomnia, abnormally folded proteins accumulate and destroy brain cells. Antisense oligonucleotides (ASOs) have traditionally been used to treat such conditions by targeting and altering protein production. These require multiple doses and can have significant side effects.

In 2021, Jonathan Weissman and his team at MIT tackled the delivery challenge of gene-editing tools, which were previously too large to be transported effectively into brain cells [2]. By using zinc-finger proteins, CHARM can be delivered using a common gene therapy vector, adeno-associated virus (AAV), enhancing its applicability.

CHARM works by recruiting elements that add methyl groups to DNA, thereby controlling gene expression while reducing toxic impacts [3]. In trials, CHARM reduced the expression of harmful proteins by over 80% throughout the mouse brain, demonstrating a significant therapeutic potential.

The potential of CHARM extends beyond prion diseases, with possibilities for treating other conditions characterized by protein accumulation, such as Parkinson’s and Alzheimer’s. However, additional investigations are needed to determine how these genetic alterations interact with cellular machinery over time.

This breakthrough brings hope not only for treating prion diseases but also for advancing gene therapy techniques against a range of neurodegenerative disorders, setting the stage for future clinical applications.

Learn more about this study published in Science.


Photograph: AnnaStills/Envato
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