Today we’re announcing the launch of PROSPECT (NCT07732608). This is a prospective, longitudinal, fully remote long-term registry study of people living at genetic risk of prion disease.

why

In my last post, I described our efforts over the past 10 years to understand the risk associated with genetic variants in the prion protein gene (PRNP). The age of onset (when) and penetrance (if) disease develops are two sides of the same coin: what is the probability of developing disease for someone with a specific PRNP gene variant, both at any specific age, and cumulatively over their lifetime? We have asked this question several different ways, using the frequency of DNA variants in cases and controls [Minikel 2016], the ages that people presented to surveillance and clinical centers [Minikel 2019], and long-term follow-up on people who previously had genetic testing [Lian & Kotobelli 2026]. These data have critically informed the current genetic counseling guidance [Goldman & Vallabh 2022] by allowing us to determine which genetic variants are high risk and which are low risk, and to have some idea of what ages the disease is most likely to strike.

Today, we turn our eyes towards the ultimate goal of preventing prion disease. There are now multiple drugs in clinical trials in symptomatic prion disease patients, and we have just seen the very beginning of these starting to be tested in pre-symptomatic people. Ultimately the goal will be to test these drugs for their ability to prevent disease. If we want to prevent prion disease, we need 3 things:

  1. Trial-ready cohort. A clinical trial-ready population of people at risk, with genetic test results, who may be interested in trials.
  2. Natural history. Quantitative estimates of when their disease would strike if not prevented. We can gather these data now, as a comparator for future data when, hopefully, people go on drugs to try to prevent the disease.
  3. Long-term monitoring plan. An infrastructure to monitor people’s cognitive health and survival over the long term, so that we can determine whether future drugs are delaying disease in the at-risk population.

PROSPECT is designed to support all of these goals.

what

PROSPECT is long-term registry study open to people who either know they have prion protein gene (PRNP) variants, or, who are untested but are at risk based on their family history. Here, a positive family history is defined as having one relative with a known PRNP variant or at least two individuals affected by prion disease without a known PRNP variant. Participants who have not already undergone genetic testing will do so as part of the study, using an at-home saliva collection kit that can be mailed in to extract DNA. Participants will be offered genetic counseling, but are not required to learn their genetic status in order to participate. The study will follow people annually over videoconference and will involve answering questions and doing standardized surveys that should only take about one hour. The goal is to collect data that will assist in determination of the lifetime risk and age of onset associated with each genetic variant, and thereby to help enable clinical trials and the development of preventive drugs for prion disease. This is an open data study: de-identified data will be shared with other researchers and with sponsors developing drugs and running clinical trials.

The study is funded by CJD Foundation and Prion Alliance. The study is run at University Hospitals Cleveland Medical Center in Cleveland, Ohio, by Principal Investigator Brian Appleby, MD. You do not need to travel to Cleveland to participate — the study is fully remote.

what’s involved

This research study requires that the study team know the genetic status of everyone in the study. Thus, all participants will be required to have genetic testing. If you have already undergone genetic testing, you can provide your existing test information to the study team. If you don’t know your genetic status, you will undergo testing, but you can still choose whether or not you want to learn your results. The testing will be done by mailing you a saliva kit. You spit into it at home and mail it to the testing lab, where they will extract and sequence your DNA. You will undergo a pre-test genetic counseling session to discuss whether you want to learn your results. If not, we will keep the results on file but not tell you, and the study staff will be blinded so that the people you interact with in the study do not know your status either. If you do want to know your status, you will have a post-test genetic counseling session to learn your results. The genetic counseling is done via telehealth visits with providers certified in all 50 U.S. states. The genetic testing and genetic counseling are done as part of this research study and are kept out of your medical record, and because the study is funded through research, nothing is billed to your insurance.

After your genetic testing, the study involves annual follow-up visits via videoconference where the study team will ask you to complete some surveys and scales. You will also be asked to have a backup contact, to whom we can reach out if we’re unable to reach you. It is important for the goals of this study to know the long-term outcomes of everyone involved, so if we lose touch with you, we will try reaching your backup contact and also search public records and available databases for any evidence of whether you passed away, potentially from prion disease.

goals

For years now, we have heard from people at risk that there are two major barriers to genetic testing:

  1. Inability to find a willing, available, knowledgeable genetic counselor licensed in their state.
  2. Fear of genetic testing results ending up in their medical record or insurance records.

PROSPECT includes genetic counseling with a telehealth genetic counselor licensed in all 50 states, with confidential genetic testing kept apart from your medical records and never billed to insurance. Therefore, PROSPECT stands to remove these major barriers. If more people choose to know their genetic status, this will enlarge the pool of people potentially available to participate in future clinical trials of drugs designed to prevent the disease.

Today, there are no drugs known to prevent or delay the onset of prion disease. PROSPECT will gather data on the ages at which people are developing disease now — in the absence of treatment. This “natural history” of the disease will help us in the future by providing a reference against which to compare whether age of onset has shifted later, or risk has shifted lower, in people who start taking experimental drugs.

In the future, when we have potentially effective drugs that we need to evaluate, we will also need a system by which to follow up people who are on drug, and determine how long they are surviving. By establishing a study infrastructure for long-term follow-up of people at risk, PROSPECT may also underpin such a system.

how to sign up

The full study listing for PROSPECT can be found at clinicaltrials.gov: NCT07732608

To learn more and ask to schedule a screening visit, please contact study coordinator Meg Verba at Margaret.Verba@uhhospitals.org or call 216-368-2062.

frequently asked questions

Q. Can I participate if I have genetic history in my family, but already tested and know that I do not have a PRNP variant?

A. No, the goal is to study people who do have a genetic variant, so only people who either know they have a variant, or remain at risk, are eligible.

Q. My parent or other relative died of prion disease, but I do not know whether they were a genetic carrier. Can I participate in the PROSPECT study?

A. If you have two family members in your family who passed from prion disease and their genetic status is unknown, then you are eligible for the study. If you have a single family member who passed from prion disease with an unknown genetic status, would not make you eligible for the study.

Q. I live outside the U.S. Can I participate in this study?

A. No, unfortunately at this time PROSPECT is U.S. only.

Q. If I enroll in the study and receive genetic testing but opt not to learn my test results, can I still participate in the annual follow-ups?

A. Yes. You do not need to learn your results to participate.