Team reaches significant milestone towards treatment for prion disease. For them, it’s personal.

Recent studies offer optimism that prion disease — a rare collection of invariably lethal maladies triggered by misfolded proteins in the brain — might, in the foreseeable future, have a remedy if not an outright cure.

The study, released earlier this year in the journal Nature Medicine, illustrated that modifying a single base in the gene responsible for producing the harmful proteins can diminish the quantity of that protein in the brains of test mice by half, a step that prolonged their lifespans by 52 percent.

The contributors to the study, located at the Broad Institute of MIT and Harvard, emphasize that multiple potentially protracted steps remain before this technique can advance to human trials. Nevertheless, they concurred that the findings suggest the approach they began pursuing nine years ago toward effective treatments for humans seems to be encouraging.

“I consider this a milestone without a doubt,” expressed David Liu, the senior author of the study, in whose laboratory the base editing technology was created. “One must tread cautiously, recognizing that the journey to a formal clinical trial demands traversing several such milestones.”

Prion disease includes various conditions that result in neurological damage and dementia, such as Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Approximately 15 percent of cases stem from a hereditary mutation in the prion protein gene, while 85 percent are “sporadic,” occurring when these proteins spontaneously assume abnormal, toxic configurations.

‘Personal’ quest for the scientist who is also a patient

While laboratory research is frequently detached from the patients it aims to assist, these experiments form part of a deeply personal quest for several of the authors of the paper. This is because one of them, HMS Assistant Professor of Neurology Sonia Vallabh, has received a positive diagnosis for a hereditary form of prion disease referred to as fatal familial insomnia.

In late 2010, Vallabh’s mother succumbed to an enigmatic, degenerative disorder that subsequent examinations confirmed as fatal familial insomnia. Shortly thereafter, Vallabh herself was found to have the mutation that causes the disease. This discovery prompted Vallabh, who had graduated from Harvard Law School, and her spouse, Eric Minikel, who holds an urban planning degree from MIT, to retrain for professions focused on comprehending and finding a treatment for prion disease. Today, the couple operates their own laboratory at the Broad, employing 14 researchers. In a relatively brief period, Liu stated, they have emerged as specialists in the therapeutically significant aspects of the ailment.

“It’s an immense privilege to collaborate with them,” remarked Liu, the Thomas Dudley Cabot Professor of the Natural Sciences in Harvard’s Faculty of Arts and Sciences and a core institute member at the Broad. “Their personal connection to the illness instills extraordinary motivation for everyone to strive to make as much advancement as we can — thoughtfully, but as efficiently as we can.”

The promising results build upon findings in Liu’s lab, which pioneered the single base editing method utilized in the experiments. That method has been applied in 13 clinical trials, Liu noted, and has been beneficial for patients suffering from hypercholesterolemia, sickle cell anemia, T-cell leukemia, and beta thalassemia.

“David took us seriously long before anyone had much reason to, so we’ve engaged in a collaboration with him for a significant time,” stated Minikel, who is also an assistant professor of neurology at Harvard Medical School. “It has been an ideal collaboration in the sense that Sonia and I have always felt a deep concern for this condition, but we are not experts in technology development. We will provide, ‘Here are the models, assays, and tools necessary to create a drug for this ailment,’ but we’re probably not the ones who will be designing the drug.”

In the present study, scientists utilized a mouse model of human prion disease, which increases the likelihood that the research will successfully translate to humans. Funded by the National Institutes of Health, the Broad, the Prion Alliance, and the Howard Hughes Medical Institute, this research involved integrating a genetic base editor developed in Liu’s lab into an adeno-associated virus, which serves as a vector that targets cells and integrates its DNA payload into their genomes. This rewrites the cellular instructions for producing the protein, in this case ceasing production.

“Having a friend, a collaborator, who could benefit from this treatment truly enhances personal motivation.”

Meirui An

Meirui An, a graduate student in Liu’s lab and one of the primary authors of the study, mentioned that sometimes the vector itself can induce illness, prompting researchers to modify that component of the process for enhanced safety, ultimately resulting in a 63 percent decrease in prion protein production despite utilizing a significantly lower dosage of the vector virus.

The dangerous and infectious nature of prions may render this research among the last undertaken with human prion protein, Liu asserted. Such studies were limited after an accidental exposure in a French laboratory resulted in a researcher’s passing due to prion disease.

Human trials for any treatment that may arise from this work are projected to be several years away, Liu indicated. Regardless of the necessary intermediary steps, researchers noted they will likely encompass fine-tuning the base editor — which is so large that it must be transported into cells in two distinct viral capsules — enhancing targeting to minimize its integration into cells of other tissue types, and improving efficiency in curbing the production of prion protein.

An and others commended the cooperative process among the involved labs, which included that of the Broad’s Benjamin Deverman, an expert in vector engineering.

“Our interactions have been quite frequent, and to me, personally, it’s extremely motivating to collaborate with patient-scientists,” An expressed. “I find no need to seek external motivation to work on this project, as just having a friend and collaborator who could benefit from this treatment significantly fuels my personal drive.”