Studies suggest that stopping this brain-wasting condition may require early intervention

This September, we’ll be speaking at the Charles River World Congress on Animal Models in Drug Discovery & Development about our quest to prevent prion disease. Our goal — prevention — is shaped both by our personal experience of prion disease and by the lessons learned from animal models. Five and a half years ago, as newlyweds with no background in biology, we received a genetic test report telling us that Sonia had inherited a fatal genetic mutation in the prion protein gene. We changed careers and became scientists in a bid to stop this disease before it claims Sonia’s life. We founded a non-profit, Prion Alliance, and we are now PhD students based at the Broad Institute of MIT and Harvard.

Compared to other neurodegenerative diseases, prion disease is uniquely rapid: most patients die within six months of their first symptom, and most of that short time is spent just reaching a correct diagnosis. By the time they are diagnosed, most patients are profoundly debilitated, and even a drug that halted the disease process entirely wouldn’t be able to reverse the brain damage they’ve suffered. It is not clear whether keeping patients alive longer at this stage would even be a benefit in many cases. Our personal goal, then, has to be to keep Sonia healthy, to prevent her from developing the disease in the first place.

Evidence from animal models suggests that this is possible. Infection with prions causes reliably fatal disease in wild-type mice, giving us excellent animal models for preclinical studies, though the prion field has seen some hard lessons along the way. Therapies that prevent prions from getting into the brain don’t necessarily work once prions are already in the brain, and therapies that work against laboratory strains of mouse prions don’t necessarily work against prions from human brains injected into the transgenic mice expressing human prion protein. Perhaps most importantly, several studies have identified molecules that dramatically delay the onset of prion disease in mice, and time and time again these studies have shown that early intervention matters. For instance, one molecule allowed prion-infected mice to survive four times as long as untreated controls, but only when given prophylactically. When that same molecule was given only after the mice began to show neurological symptoms, it did nothing.

This raises a chilling prospect: we could do drug discovery exactly right, and be holding in our hands a drug that would extend Sonia’s life by decades, but if we put it into a clinical trial in symptomatic patients, we could wrongly convince ourselves that it does nothing. If we want a preventive drug, then a preventive trial is essential. Having the right animal model, and doing the right preclinical studies, doesn’t merely serve as a gate to decide which therapies deserve to go into clinical trials. It can reorient the whole preclinical enterprise around preparing for how to do the right clinical trial.

In our case, we need to begin reaching out to the patient community to identify other people who, like us, want to see a preventive therapy, and are willing to participate in preventive trials. So we’ve launched an online registry to connect patients and people at risk with opportunities to participate in prion research. We will need a biomarker that we can measure in healthy patients to determine whether a drug is having its intended effect. So we’ve begun collecting and analyzing cerebrospinal fluid samples from collaborators around the world, and have launched a research study at Massachusetts General Hospital to collect new samples from people at risk for genetic prion disease. And, inevitably, we will need many more preclinical studies in the right animal models, to make sure that we understand a potential drug’s mechanism of action, its effects on relevant biomarkers, and when and how it can be used effectively. 

This September, the Inaugural Charles River World Congress on Animal Models in Drug Discovery & Development will explore how to use clinical data to develop translatable models for drug discovery. There, Sonia Vallabh and Eric Minikel will receive the Charles River Annual Research Models in Drug Discovery Award. Register today by visiting: http://breakthroughs.criver.com/.