New paradigms of clinical trial design for genetic prion diseases

Genetic prion diseases comprise a relatively small fraction (10–15%) of all prion diseases, the most common being sporadic Creutzfeldt-Jakob disease.1 Since no therapy exists except palliation, individuals with family history of genetic prion disease face the dilemmatic decision of whether to undergo genetic testing. Because of phenotypic variability of genetic prion diseases and the paucity of biomarkers that predict clinical onset, sufficiently powered clinical trials would require several hundreds of individuals—an unrealistic scenario given the rarity of these diseases. Mice devoid of Prnp, the gene encoding PrPC, are resistant to prion diseases, and crucially hemizygosity for Prnp conspicuously prolongs latency time of disease.4 To reduce PrPC concentrations in brains of PRNP mutation carriers, Vallabh and colleagues propose a prophylactic treatment regimen using ASOs against PRNP in the framework of an Accelerated Approval procedure by the FDA. Most individuals with genetic prion diseases are aware of their mutation years or even decades before symptom onset, making them ideally suited for the prophylactic trial.2 Likewise, carriers of autosomal-dominant mutations in the PSEN1 gene, manifesting as Alzheimer's disease, are part of a preventive placebo-controlled trial involving the anti-β-amyloid antibody, crenezumab.10 However, PSEN1 mutations are more prevalent than are PRNP mutations and have a more predictable clinical course.10 Last, this trial is personal: