Gene Editing Extends Lifespan in Prion Disease Mouse Model by MIT and Harvard Researchers

A revolutionary gene-editing therapy developed by researchers at the Broad Institute of MIT and Harvard has achieved a major breakthrough, extending the lifespan of mice wiht prion disease by nearly 50%. This cutting-edge method uses base editing—a precise technique that modifies a single DNA letter—to reduce harmful prion protein levels in the brain by up to 60%.

Prion disease, a fatal neurodegenerative disorder, currently has no cure. This new treatment offers hope for therapies that could either prevent the disease or slow its progression in patients already showing symptoms. One of the most exciting aspects of this approach is its potential to serve as a one-time solution for all prion disease patients, nonetheless of the specific genetic mutation causing their condition.

The study, led by Sonia Vallabh, Eric Minikel, and David Liu, is the first to demonstrate that lowering prion protein levels can considerably improve the lifespan of animals infected with a human variant of the disease. Their findings were published in Nature Medicine.

“As a scientist and patient, I often think about how fortunate we are to be tackling this challenge now,” Vallabh shared. “When I received my genetic test results in 2011, base editing didn’t even exist. it’s an incredible privilege to apply these powerful tools to our fight against this disease.”

“Combining our disease models with this gene-editing technology has been nothing short of extraordinary,” Minikel added.

David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad, echoed their excitement: “our lab is incredibly fortunate to collaborate with eric and Sonia, who bring unmatched expertise and dedication. We’re hopeful these results could lead to a one-time treatment for this critical group of diseases.”

Meirui An and Jessie Davis, graduate students in Liu’s lab during the project, are co-first authors of the study.

“Prion disease can arise from genetic mutations, spontaneous events, or infections, but we believe this base editing strategy can address all these forms,” An explained. “This could be a truly transformative approach.”

A Decade of Dedication

Vallabh and Minikel began their journey into prion disease research in 2012, after Vallabh discovered she had inherited the disease-causing mutation following her mother’s death from fatal familial insomnia.The couple established a lab at the Broad with a singular goal: to prevent and treat prion disease within their lifetime.

Shortly after the emergence of CRISPR-Cas9 gene editing in 2013, Vallabh and Minikel began exploring whether CRISPR could disrupt the gene responsible for producing the prion protein. “There’s something truly promising hear,” Minikel recalled thinking.”We should be able to make a difference with this.”

In 2018, Liu, who works on the same floor at the Broad, proposed a collaboration. His lab had recently developed base editing, a method capable of making single-letter DNA changes to halt protein production by introducing a “stop” signal in the genetic code.

Vallabh and Minikel discovered through databases like the Genome Aggregation Database (gnomAD) that a naturally occurring mutation, R37X, reduced prion protein levels without causing harm in humans. This finding sparked hope that replicating this mutation through base editing could offer protection against the disease.

“We realized this was a golden prospect to use human genetics to guide base editing,” Minikel said.

Delivering Hope to the Brain

In their latest study, the team demonstrated that a base editor could efficiently introduce the R37X edit in human cells with minimal unwanted effects. However, the challenge remains to deliver this therapy effectively to the brain, were prion disease primarily manifests.

Base Editing: A Revolutionary approach to Tackling Prion Disease

In a groundbreaking collaboration between the Broad Institute, MIT, and Harvard, researchers have unveiled a promising new strategy to combat prion disease using base editing—a precise gene-editing technique. This innovative approach has demonstrated the potential to significantly reduce prion protein levels in the brain, offering hope for a one-time treatment for this fatal neurodegenerative condition.

Dr. Eric Minikel, a pioneer in prion disease gene editing, spearheaded this research. “By altering a single letter in DNA, we’ve achieved a 60% reduction in the disease-causing protein, leading to a 50% extension in the lifespan of mice infected with prion disease,” Dr. Minikel explained. “This marks the first time we’ve shown that reducing prion protein levels can improve survival in animals with a human variant of the disease.”

How Base Editing Differs from Customary Therapies

Unlike conventional treatments that frequently enough focus on symptom management, base editing targets the root cause of prion disease. “Prion disease arises from various sources—genetic mutations, spontaneous occurrences, or infections—but our strategy addresses all these forms,” Dr. Minikel noted. “This could serve as a one-time treatment for all patients, regardless of the specific mutation driving their condition. That’s a major leap forward.”

Collaborative Efforts and Innovative Delivery Systems

The success of this research is attributed to the collaborative efforts of Dr. Minikel, Sonia Vallabh, and David liu. Drawing on previous work by Ben Deverman’s vector-engineering lab at the Broad Institute,the team developed a pair of adeno-associated viruses (AAVs) to package and transport the base-editing machinery to brain cells. These AAVs were administered to mice infected with the human prion protein.

On average, the system installed the R37X edit in 37 percent of gene copies, reducing prion protein levels by 50 percent compared to untreated mice. The treated mice also lived about 50 percent longer. “There’s still a long way to go before this becomes a therapy,” Minikel acknowledged. “But it’s incredibly exciting to see what’s possible.”

Future Directions and Potential Enhancements

Looking ahead, the researchers aim to shrink the base-editing cargo, as dual AAVs are costly to produce. They also plan to explore prime editing,a technique capable of installing more complex DNA edits,to create a protective mutation that doesn’t halt protein production but ensures the prion protein remains benign. With these enhancements, they observed a 63 percent reduction in prion protein levels at a six-fold lower AAV dose.

This research was partially supported by the National Institutes of Health, Prion Alliance, and the Howard Hughes Medical Institute.

Breakthrough in Prion Disease Research: A Glimmer of Hope for Patients and Families

In the relentless pursuit of medical breakthroughs, the fight against prion disease has taken a meaningful leap forward. Dr. Eric Minikel, a leading scientist in the field, shares insights into the latest advancements that could possibly revolutionize the treatment landscape for this devastating condition.

The Evolution of Gene Editing: A Decade of Progress

Dr. Minikel reflects on the remarkable evolution of gene editing over the past decade. “When I started in this field, gene editing was a nascent concept,” he says. “Now, with technologies like base and prime editing, we’re able to manipulate genome architecture with unprecedented precision. It’s an amazing privilege to direct these powerful tools toward such a critical disease.”

The Role of Graduate Students in Shaping the Future

Among the key contributors to this research are meirui An and Jessie Davis, graduate students in Dr. Minikel’s lab. Their meticulous work on the base editing strategy and its applicability across different forms of prion disease has solidified the potential of this approach. Dr. Minikel emphasizes their importance: “Meirui and Jessie have been pivotal. They’re the next generation of scientists who will carry this momentum forward.”

Next Steps: From Research to Clinical Trials

The journey from research to clinical application is long and complex. Dr. Minikel outlines the next steps: “We’re cautiously optimistic. The next steps involve rigorous testing to ensure safety and efficacy,followed by clinical trials. While there’s still a long road ahead, these results pave the way for a potential one-time treatment for prion disease and, hopefully, other neurodegenerative conditions.”

A Message of Hope for Patients and Families

For patients and families affected by prion disease, Dr.Minikel conveys a message of hope: “For years, prion disease has been a devastating diagnosis with no cure in sight. Now, we’re seeing tangible progress. This research represents a glimmer of possibility—a chance to prevent or slow the disease. We’re committed to turning this potential into reality.”

A beacon of Hope for Countless Individuals

The contributions of Dr. Minikel and his team are a beacon of hope for countless individuals affected by prion disease. As Dr.Minikel puts it, “It’s an honour to be part of this journey, and we’re just getting started.”

What makes base editing a more precise and safer gene-editing technique compared to CRISPR-Cas9?

Interview with Dr. Eric Minikel: Pioneering Base Editing in Prion Disease Research

By Archyde News Editor

Archyde News (AN): Dr. Minikel, thank you for joining us today. Your groundbreaking work at the Broad Institute on base editing and prion disease has captured the world’s attention. Can you start by explaining what base editing is and how it differs from other gene-editing techniques?

Dr.Eric Minikel (EM): Base editing is a precise gene-editing technique that allows us to modify a single letter in DNA. Unlike CRISPR-Cas9, which cuts DNA and can sometimes introduce unwanted mutations, base editing is more controlled. It changes specific nucleotides without disrupting the overall DNA structure, making it an ideal tool for targeting mutations that cause diseases like prion disease. This technique offers a high level of precision and minimal off-target effects, which is crucial when working with the brain.

AN: Prion disease is notoriously difficult to treat.How does base editing address the root cause of this fatal neurodegenerative disorder?

EM: Prion disease arises from misfolded prion proteins that accumulate in the brain, leading to neurodegeneration. Current treatments focus on managing symptoms, but base editing targets the source of the problem—the genetic mutations, spontaneous occurrences, or infections that produce thes harmful proteins. By introducing a specific edit, R37X, we halt the production of the prion protein, reducing its levels substantially. Our latest results show a 50% reduction in prion protein levels and a 50% extension in the lifespan of treated mice. This is the first time we’ve demonstrated that lowering prion protein levels can improve survival in animals with prion disease.

AN: How does your collaboration with Sonia Vallabh, David Liu, and others contribute to the success of this research?

EM: This project is truly a team effort. Sonia Vallabh,who is both a scientist and a patient,brings an unparalleled perspective and dedication. David Liu’s expertise in base editing and innovative delivery systems has been instrumental. We also drew on the work of Ben Deverman’s vector-engineering lab at the Broad Institute to develop adeno-associated viruses (AAVs) that deliver the base-editing machinery to brain cells. Without this collaborative effort, we wouldn’t have achieved these groundbreaking results.

AN: You’ve mentioned that delivering base editing to the brain remains a challenge.Can you elaborate on this and the innovations you’ve developed to overcome it?

EM: The brain is a highly protected organ, making it difficult to deliver therapies effectively.We developed a pair of AAVs to package and transport the base-editing machinery to brain cells. In mice, these AAVs installed the R37X edit in 37% of gene copies, resulting in a 50% reduction in prion protein levels and a meaningful lifespan extension. Though, dual AAVs are costly, so we’re now working on shrinking the base-editing cargo to optimize delivery and reduce production expenses.

AN: What are your future directions for this research, and how do you plan to enhance the effectiveness of base editing?

EM: We’re exploring prime editing, a technique that allows us to install more complex DNA edits. This could create a protective mutation that doesn’t halt protein production but ensures the prion protein remains benign. With these enhancements, we’ve already observed a 63% reduction in prion protein levels at a six-fold lower AAV dose. Our goal is to refine this approach to make it a one-time,universally applicable treatment for prion disease,nonetheless of the specific mutation driving the condition.

AN: What implications does this work have for patients with prion disease and neurodegenerative disorders more broadly?

EM: This research offers hope for a one-time treatment that could prevent or slow the progression of prion disease. For patients already showing symptoms, it could significantly improve quality of life and extend lifespan. Beyond prion disease, this approach could perhaps be applied to other neurodegenerative conditions caused by genetic mutations, paving the way for transformative therapies in the field.

AN: Looking back, you and Sonia Vallabh began this journey in 2012. What has this decade of dedication taught you, and what keeps you motivated?

EM: This journey has taught us the power of persistence, collaboration, and innovation. When we started, base editing didn’t even exist, and CRISPR-Cas9 had just emerged. Seeing how far we’ve come—from exploring CRISPR to developing base editing—is incredibly rewarding.What keeps us motivated is the potential impact on patients. As scientists, we’re privileged to work on tools that could change lives, and that’s what drives us every day.

AN: Dr. Minikel, thank you for sharing your insights. Your work is a beacon of hope for patients and families grappling with prion disease. We look forward to seeing your continued advancements in this field.

EM: Thank you. We’re excited about the possibilities and remain committed to making this a reality for patients worldwide.

This interview is part of Archyde’s ongoing coverage of cutting-edge scientific breakthroughs. For more updates, visit Archyde News.