Rationale for early therapeutic intervention in genetic prion disease

Abstract

Prion disease is a fatal, incurable neurodegenerative disease caused by a conformational change in the prion protein (PrP). Reducing brain PrP expression is a well-supported therapeutic strategy, and may be achievable in humans using intrathecally delivered antisense oligonucleotides (ASOs). Preclinical evidence indicates that some therapies may be more effective, or may only be effective, before symptom onset. Predictive genetic testing provides an opportunity to intervene early and preserve full quality of life in healthy individuals with prion protein gene (PRNP) mutations. Here, we report four advances that simultaneously strengthen the rationale for clinical trials in these pre-symptomatic individuals, and provide key data to enable such trials. First, by comparing allele frequencies in prion disease cases and population controls, we quantify PRNP variant penetrance and determine which individuals are at high lifetime risk — a potential patient population for trials. We also characterize healthy humans with heterozygous PRNP loss-of-function variants, supporting the safety of PrP-lowering strategies. Second, we characterize age of onset in genetic prion disease, and show that randomization to a disease endpoint is infeasible. This motivates development of biomarkers as surrogate endpoints, and our natural history dataset could aid in long-term confirmation of clinical benefit. Third, we develop a method for quantifying cerebrospinal fluid (CSF) PrP by mass spectrometry. CSF PrP decreases in active prion disease, potentially confounding any pharmacodynamic readout for a PrP-lowering drug in symptomatic patients, thus further motivating pre-symptomatic trials. Accordance between mass spectrometry and immunoassay results builds confidence in CSF PrP as an analyte, supporting its use as a biomarker. Fourth, we assess the efficacy of PrP-lowering ASOs against established brain prion infection in mice. We observe efficacy even at timepoints with detectable neuropathology and near the onset of obvious symptoms, encouraging further development of this modality. We also find that efficacy is maximized when treatment is initiated earlier, emphasizing the need to establish a clinical pathway for pre-symptomatic trials. Our findings help to establish both the need for, and feasibility of, early therapeutic intervention in genetic prion disease.