Drug development is a notoriously slow process, often taking decades to translate basic research discoveries into widely available treatments. This timeline can feel agonizingly long for individuals battling fatal diseases, a sentiment acutely understood by Sonia Vallabh, a senior group leader at the Broad Institute of MIT and Harvard. Vallabh’s research focuses on fatal familial insomnia, a devastating prion disease she is genetically predisposed to develop.
Vallabh and her husband, Eric Minikel, embarked on their research careers after learning about her genetic risk and the lack of effective treatments for prion diseases. Their lab at the Broad Institute is dedicated to developing therapies for these conditions, driven by a deeply personal deadline woven into Vallabh’s DNA.
This sense of urgency led them to collaborate with Jonathan Weissman, a member at the Whitehead Institute for Biomedical Research, known for his group’s rapid pace of work. In under two years, their collaboration has yielded CHARMs (Coupled Histone tail for Autoinhibition Release of Methyltransferase), a set of molecular tools capable of silencing disease-causing genes, including the prion protein gene. While still in the early stages of development, CHARMs hold immense potential for treating a range of genetic diseases.
“The spirit of the collaboration since the beginning has been that there was no waiting on formality,” Vallabh shares. “As soon as we realized our mutual excitement to do this, everything was off to the races.”
The team’s findings, published in Science, detail the development of CHARM and its potential applications. Weissman, also a professor of biology at MIT and a Howard Hughes Medical Institute Investigator, emphasizes the unique research environment that facilitated this rapid progress: “With the Whitehead and Broad Institutes right next door to each other, I don’t think there’s any better place than this for a group of motivated people to move quickly and flexibly in the pursuit of academic science and medical technology. CHARMs are an elegant solution to the problem of silencing disease genes, and they have the potential to have an important position in the future of genetic medicines.”
Prion diseases, characterized by rapid neurodegeneration, are caused by misfolded prion proteins that disrupt normal brain function and lead to neuronal death. While some forms are infectious, others are inherited or arise spontaneously. Current treatment options are limited, making the development of effective therapies crucial.
Unlike traditional drugs that target proteins, CHARMs work upstream by switching off the genes responsible for producing faulty proteins. This is achieved through epigenetic editing, a process that adds chemical tags to DNA to silence specific genes without altering the underlying genetic code. This approach offers a potentially permanent solution, unlike protein-targeting drugs that require continuous administration.
Building upon their previous work on CRISPRoff, a gene-silencing tool, the team engineered CHARM to be smaller, safer for human use, and less likely to cause unintended gene silencing. They replaced the bulky Cas9 protein with a smaller zinc finger protein (ZFP) and devised a mechanism to recruit the cell’s own DNMT3A enzyme for methylation, enhancing efficiency and reducing toxicity.
“From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution,” explains Edwin Neumann, a graduate student in Weissman’s lab and co-first author of the study. “Cells are already using methyltransferases all of the time, and we’re essentially just tricking them into turning off a gene that they would normally leave turned on.”
Animal studies have shown promising results, with CHARMs successfully eliminating over 80% of the prion protein in the brains of mice. Notably, previous research suggests that even a 21% reduction can alleviate symptoms. To further enhance safety, the researchers designed CHARM to deactivate itself after silencing the target gene, minimizing the risk of long-term side effects. Additionally, a parallel study from collaborator Benjamin Deverman’s lab at the Broad Institute, published in Science, focused on developing an AAV vector capable of delivering CHARM efficiently to the brain, a significant hurdle in treating brain-wide diseases like prion disease.
The team is now refining CHARM for increased efficacy, safety, and scalability in preparation for clinical trials. They have created a modular design, allowing for easy modification and adaptation for targeting different genes.
While the journey from research to clinical application is arduous, the researchers remain optimistic. Their innovative approach, coupled with promising preliminary results, offers a beacon of hope for individuals and families affected by prion diseases. The team’s unwavering commitment to developing CHARM as a viable treatment option underscores their dedication to turning scientific breakthroughs into life-saving therapies.
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