# Potent Therapy Candidate for Fatal Prion Diseases: Exploring Promising Treatment Options
Scientists have created a gene-silencing tool that shows potential as a therapy for fatal prion diseases. The streamlined epigenetic editor opens doors to a new category of genetic methods to address specific illnesses.
Drug development can be a slow process, taking decades from initial research breakthroughs to clinical trials and the production of widely available medications. However, for individuals suffering from fatal diseases, the wait can seem insurmountable. Broad Institute Senior Group Leader, Sonia Vallabh, understands this urgency firsthand. Her research focuses on fatal familial insomnia, a type of prion disease she is likely to develop due to carrying a disease-causing version of the prion protein gene. Vallabh and her husband, Eric Minikel, transitioned to research careers after learning that no effective therapies exist for fatal prion diseases. They now lead a lab at the Broad Institute aiming to develop drugs for preventing and treating these diseases, with the looming deadline based on the genetic predisposition in Vallabh’s code rather than typical academic timelines or grant cycles.
Vallabh’s collaboration with Whitehead Institute Member, Jonathan Weissman, resulted in the creation of a set of molecular tools known as CHARMs. These tools can deactivate disease-causing genes, such as the prion protein gene, and potentially other genes linked to neurodegenerative and other illnesses. While the tools must undergo further testing as potential therapeutics, the research team is encouraged by the rapid progress made in developing this technology.
CHARMs, short for Coupled Histone tail for Autoinhibition Release of Methyltransferase, are described in a paper published in the journal Science on June 27 by co-corresponding authors Weissman and Vallabh, along with co-first authors Edwin Neumann and Tessa Bertozzi from Weissman’s lab.
Prion diseases trigger rapid neurodegeneration and fatality by producing misshapen prion proteins that disrupt other proteins in the brain, leading to dysfunctional protein formation and toxic aggregates that harm neurons. While traditional drugs target proteins, CHARMs operate upstream by deactivating the genes responsible for these proteins, preventing their production. Through epigenetic editing, CHARMs add a chemical tag to DNA to silence the targeted gene without altering the gene itself. This editing method is stable, ensuring that the gene remains inactive, potentially requiring only a single CHARM treatment compared to frequent dosing with protein-targeting medications.
Research suggests that removing the prion protein is beneficial in cases of prion disease, and epigenetic editing shows promise in treating genetic diseases like inherited prion diseases. The challenge lies in developing this novel therapy, building upon the success of CRISPRoff, a gene-silencing research tool from Weissman’s group that provided a foundation for CHARMs.
To address limitations of CRISPRoff for human therapy, Neumann and Bertozzi led efforts to optimize CHARMs. They focused on downsizing the tool for efficient delivery into specific cells within the body, particularly the brain. Substituting the bulky Cas9 guide protein with a smaller zinc finger protein (ZFP) enabled a more compact design suitable for gene delivery while diminishing the risk of immune responses compared to using bacterial Cas9.
Additionally, the team redesigned the gene-silencing component of the tool, replacing it with a modified version of DNMT3A, a methyltransferase molecule that attaches methyl groups to DNA. By adapting the tool to recruit the cell’s own DNMT3A, toxic effects were averted, and space within the gene-delivery vehicle was conserved. Activating DNMT3A within the cell further optimized the CHARMs tool by preventing unintended methylation of crucial genes that must remain active.
The journey from research tool to potential drug candidate has demonstrated the progress made in overcoming obstacles to develop a promising therapy for fatal prion diseases, offering hope for improved treatments in the future.Researchers have found a clever way to silence the prion protein gene by combining DNMT3A’s partner molecules and ZFPs. This combination triggers the cell’s DNMT3A to deactivate the gene, significantly reducing the prion protein in mice.
To address off-target effects, the researchers modified the CHARM tool to self-destruct after silencing the gene, preventing unnecessary side effects. Another promising development is a new AAV vector that efficiently delivers CHARMs to the brain, paving the way for clinical trials.
The CHARM technology shows great potential as an effective and safe epigenetic editor for treating brain diseases like prion disease. Collaborative efforts have proven essential in advancing this research rapidly towards therapeutic applications.
Looking ahead, the research team is focused on optimizing CHARMs for clinical use by enhancing effectiveness, safety, and scalability. They have modularized the tool for easy customization and are conducting tests in mice to refine its therapeutic potential.
Although there are still hurdles to overcome before CHARMs can be used as a medical treatment, the researchers are optimistic about its prospects. Their dedication to innovation and patient care drives them to expedite the development of this technology for the benefit of those with prion diseases and other genetic conditions.
