Of the thousands of proteins that form the molecular machinery of our bodies, prion disease is caused by just one: the prion protein, or PrP. Many years of experiments by different labs around the world have shown us that prion disease occurs when PrP changes shape into a so-called “prion,” and recruits other copies of PrP to do the same. PrP is at the heart of all cases of prion disease — whether they are sporadic, genetic or acquired; and whether they are called Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), or Gerstmann-Sträussler-Scheinker disease (GSS). Without PrP, prion disease can’t occur.
What does this mean for us? Prion disease poses many unsolved mysteries, but the molecular simplicity at its heart has given us our therapeutic roadmap. Our job is to go straight to the heart of the disease by targeting PrP and lowering its levels in the brain. In the near term, we believe that the most realistic way to do this will be to target and destroy PrP’s RNA precursor.
In the longer run, other strategies for reducing PrP in the brain can also be imagined. Our goal is to use established therapeutic technologies to bring an effective PrP-lowering therapeutic to patients as quickly as possible, while also keeping one eye on the future.
- Antisense oligonucleotides extend survival of prion-infected mice
- Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints
Measuring our impact
To show that a drug works, we must have a way to measure its effect. Sometimes the effect is immediately obvious: a person feels better, or stops getting worse. Another way to measure a drug’s impact is go beneath the surface and look for changes at the molecular level. For a PrP-lowering drug, we have been exploring the potential of PrP levels in spinal fluid to serve as a so-called “biomarker” that tells us that the drug is doing what we need it to do, in a relevant part of the body.
Besides helping us monitor drug activity, biomarkers can help us understand and measure the disease processes. Molecular changes may be more consistent from person to person than the disease symptoms we see on the surface, and can give us insight into what exactly is going wrong, and when. Like markers of drug activity, biomarkers of disease have the potential to be useful in clinical trials, as we try to understand as fully as possible what a drug is doing in the body. To this end, we measure markers of interest in spinal fluid and blood samples donated by prion disease patients, healthy volunteers, and individuals living at risk for genetic prion disease.
- Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development
- Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease
Meeting the different needs of different patient populations
In prion disease we have two different patient populations: patients who are diagnosed after symptom onset, and individuals at risk for genetic prion disease who can be identified while still healthy. These groups have different needs: treatment for active disease on the one hand, treatment to delay or ideally prevent disease altogether on the other.
The goals of treatment and prevention are distinct, but overlapping. Both groups share the same molecular enemy, and to that end, we believe that for both, targeting PrP is the most promising therapeutic strategy available today. This may mean that same drug molecules may deserve to be tested in both populations. But given the vast differences in health status between symptomatic prion disease patients and healthy individuals at risk, we cannot take for granted that a drug will have the same effect in both populations. To fully understand a PrP-targeting drug and who it has the potential to help, we will need to test it separately for its ability to treat and to prevent disease.
Clinical trials are usually done in sick patients, and have been done in sick prion disease patients before, but testing new drugs in healthy people at risk is unusual. We are therefore working with allies across sectors to develop new tools and approaches. Our goal is to lay out a path for prevention of genetic prion disease that will be acceptable to patients, doctors, and regulators.
To help people at risk for genetic prion disease, ideally before disease strikes, we have to know as much as possible about risk. Among other questions, this means understanding who is at risk, how great that risk is, and when in life disease is likely to strike. Genetic prion disease is caused by mutations in the prion protein gene, or PRNP, that encodes the prion protein, PrP. By understanding variation in this gene, both in genetic prion disease patients and in the population at large, we can derive risk estimates to guide clinical trial design, genetic counseling, and someday, treatment paradigms. Population-level datasets can also provide glimpses of “experiments of nature:” individuals in whom PrP level has been modulated by chance, who provide human data with which to vet our therapeutic goal of lowering PrP. Meanwhile, by studying characteristics of genetic prion disease patients, including age of onset, we can both help individuals understand their risk today, and establish a baseline against which a drug-treated population can someday be compared.
- Quantifying prion disease penetrance using large population control cohorts
- Age at onset in genetic prion disease and the design of preventive clinical trials
- Evaluating drug targets through human loss-of-function genetic variation
For more information, please see the list of our research works and publications.