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Use of Prion Protein Biomarker in Prion Disease Therapy Clinical Trials

Key findings

  • This interim analysis reports on 27 individuals with presymptomatic genetic prion disease and 16 noncarrier controls who were evaluated to identify biomarkers for primary and secondary prevention trials of prion protein (PrP)-lowering drugs
  • Levels of PrP in cerebrospinal fluid (CSF) were stable over the short term (two to four months), and in a pilot longitudinal study of 10 participants, they remained stable over 10 to 20 months
  • Markers of neuronal damage and prion seeding activity did not reliably distinguish mutation carriers from controls
  • The stable levels of CSF PrP in pre-symptomatic prion mutation carriers validates it as a meaningful biomarker for primary prevention trials with PrP-lowering therapeutics

Prion protein (PrP) is now well established to be the sole cause of prion disease, and PrP-lowering therapeutics are in preclinical development. As investigators plan for clinical trials, they face the challenge that prion disease is a rapidly progressive and invariably fatal disease, and symptomatic patients are usually profoundly debilitated by the time of diagnosis and trial enrollment.

One alternative may be to conduct prevention trials in individuals with mutations in the prion protein gene (PRNP), who may be aware of their risk decades before symptom onset. However, age of onset is highly variable in genetic prion disease, so rather than having disease onset be the endpoint of a drug trial, a biomarker is needed to serve as a surrogate endpoint.

Researchers Sonia M. Vallabh, PhD, and Eric Vallabh Minikel, PhD, of the Broad Institute, Steven E. Arnold, MD, managing director of the Interdisciplinary Brain Center at Massachusetts General Hospital, and colleagues are conducting a longitudinal cohort study to evaluate biomarkers that might predict clinical benefit in presymptomatic genetic prion disease. They recently described promising interim results in BMC Medicine.

Study Details

The paper reports on 27 pre-symptomatic individuals who carry PRNP mutations and 16 demographically matched controls, average age 44. Both the carrier and control groups had normal scores on a battery of 20 cognitive, neuropsychological, psychiatric and motor tests.

The team measured biomarkers cross-sectionally, evaluated test–retest reliability over two to four months and conducted a pilot longitudinal study.

PrP Levels

Cerebrospinal fluid (CSF) PrP levels were stable over two to four months (average coefficient of variance [CV], 6.8% in carriers and 7.5% in controls). In ten individuals who completed a third study visit after 10 to 20 months, CSF PrP levels remained steady (CV, 7.2%).

Markers of Neuronal Damage

In plasma:

  • Total tau was too variable over two to four months to be useful (CV, 38%)
  • Neurofilament light (NfL) protein was more reliable (CV, 18%) but not significantly different between carriers and controls


  • Levels of tau and NfL were similarly low in carriers and controls
  • In the longitudinal study, levels of both markers remained low

Prion Seeding Activity

CSF samples were negative for prion seeding activity in the non-carrier controls and in 22 of the 23 pre-symptomatic carriers.

In the one asymptomatic carrier with positive prion seeding activity, neuronal damage markers were only slightly higher than in other participants and within the range of aged healthy controls. The markers were well below typical values for patients with symptomatic prion disease. Despite the presence of prion seeding activity, CSF PrP levels were stable over a two month period in this individual. This finding suggests the decline in CSF PrP levels seen in symptomatic disease probably emerges later in the disease process and should not confound CSF PrP stability in presymptomatic carriers without observable pathology.

A Useful Marker for Clinical Trials

CSF PrP levels are stable enough in any individual, regardless of PRNP mutation, to report on the pharmacodynamics of a PrP-lowering drug.

However, the findings with current disease stage biomarkers suggest that secondary prevention trials (involving presymptomatic individuals with prodromal biomarker evidence of genetic prion disease) may not be feasible at this time. Based on current knowledge, the prodromal period is likely to be too subtle, too brief or present in too few individuals at any given time to enable recruitment of an adequately large prodromal cohort.

Instead, investigators may wish to consider primary prevention trials (recruiting presymptomatic individuals at known high genetic risk without requiring prodromal pathology) and treat toward CSF PrP levels.

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