Extending Lifespan by 50% Through Base Editing Therapy

In 2010, Sonia Vallabh witnessed her 52-year-old mother develop a rapidly progressive, mysterious, and undiagnosed dementia, and soon died from it. A year later, she learned that her mother had a hereditary prion disease, fatal familial insomnia. After undergoing genetic testing, Sonia learned that she also carried the disease-causing gene mutation, which meant that she herself was likely to suffer from this prion disease. More importantly, this fatal disease usually develops around the age of 50 and quickly leads to death, and there is no cure.

Unwilling to sit and wait for death, they decided to give up their current jobs and studies and study life sciences from scratch. In 2015, they were admitted to Harvard Medical School for doctoral studies and received their doctoral degrees in biomedical sciences in 2019. Since then, they have established a laboratory at the Broad Institute, focusing on developing treatments for the prevention and treatment of prion diseases during their lifetime. In the past few years, they have published a number of high-level research papers in journals such as Nature, Science, and Science Translational Medicine, bringing new hope for the treatment of prion disease.

In January 2025, Sonia Vallabh and Eric Minikel, together with Professor Liu Ruqian, published a research paper entitled "In vivo base editing extends lifespan of a humanized mouse model of prion disease" in the top international medical journal Nature Medicine. Through in vivo base editing, the study successfully reduced the pathogenic prion protein in the brain of the humanized mouse model of prion disease by 60% and extended its lifespan by 50%. This is also the first time that it has been proven that reducing prion protein levels can extend the lifespan of animals infected with human prion protein.

Prion disease has many different origins - some are inherited, some occur spontaneously, and some are caused by infection. There is currently no cure for prion disease. This study is an important step in preventing or slowing the progression of the disease in patients with prion disease who have already developed symptoms. In vivo base editing therapy has the potential to provide a one-time treatment for patients with all types of prion diseases of different origins.

In humans, four prion diseases have been identified - kuru, Creutzfeldt-Jakob disease, GSS syndrome, and fatal familial insomnia. These fatal neurodegenerative diseases can occur spontaneously, be inherited, or even be acquired through transmission (e.g. cannibalism). All prion diseases are caused by a single molecular mechanism. That is, they are all caused by the conformational change of the prion protein (PrP) encoded by the PRNP gene from its intrinsic folded form (PrPC) to a self-replicating misfolded form (PrPSc), which can cause devastating neurodegenerative diseases.

Although there is currently no effective treatment for prion disease, studies have shown that reducing the level of prion protein in the brain of experimental animals can prevent disease progression with minimal side effects. In addition, prion protein is non-essential in mammals. Therefore, reducing the expression level of prion protein in the brain is a viable therapeutic strategy.

When Sonia Vallabh and Eric Minikel were studying medicine from scratch to try to save themselves, CRISPR-Cas9 gene editing technology was born. From then on, they began to wonder whether CRISPR technology could be used to destroy the gene encoding prion protein to prevent or treat prion disease.

In 2016, Professor Liu Ruqian developed a new generation of gene editing technology, Base Editing, which can accurately edit a single base in the genome without causing a double-strand break in DNA. Compared with CRISPR-Cas9, it is safer and more accurate. In 2018, Professor Liu Ruqian found Sonia Vallabh and Eric Minikel to cooperate and began to try to use base editing technology to terminate the expression of prion protein, thereby preventing and treating prion disease.

Sonia Vallabh and Eric Minikel found that a naturally occurring point mutation in the gene encoding prion protein (PRNP gene) - R37X, would lead to reduced protein levels without harmful side effects to the human body. This lays the foundation for the use of base editing to prevent and treat prion diseases. The research team first confirmed in human cells that the base editor (BE3.9max) can effectively edit PRNP R37X in human cells. Next, the research team began to try to deliver the base editor to the brain. The research team used the AAV virus serotype PHP.eB, which can cross the blood-brain barrier.

Figure 1. Development of initial base editing strategies to install stop codon in PRNP locus. (An M, et al., 2025)

In a humanized prion disease mouse model, the base editor BE3.9max delivered by the dual AAV vector PHP.eB had an editing efficiency of 37% for PRNP R37X. The expression level of prion protein in the mouse model brain decreased by 50%, and lifespan was extended by 52%.

Next, the research team engineered the base editing system to improve its editing efficiency in vivo and reduce base editor expression in non-target tissues. The modified base editing system reduced prion protein in the mouse model brain by an average of 63%, while the required AAV viral vector dose was reduced to less than one-sixth of the previous one, and no obvious off-target editing was detected in human cells or mice. These findings support the use of in vivo base editing for a one-time treatment of prion disease.

Sonia Vallabh said, "As a prion disease patient and a scientist, I often think about how lucky we are to have this problem now. When I received a genetic test report in 2011 that I might have hereditary prion disease, the world had not heard of base editing." Now, it is a great honor to have the opportunity to use this powerful new tool for our disease.

Eric Minikel said that the base editing system developed in this study is still a long way from becoming a treatment for prion disease, but it is really exciting to see that it has such great potential.