Age at onset in genetic prion disease and the design of preventive clinical trials

Eric Vallabh Minikel; Sonia M Vallabh; Margaret C Orseth; Jean-Philippe Brandel; Stéphane Haïk; Jean-Louis Laplanche; Inga Zerr; Piero Parchi; Sabina Capellari; Jiri Safar; Janna Kenny; Jamie C Fong; Leonel T Takada; Claudia Ponto; Peter Hermann; Tobias Knipper; Christiane Stehmann; Tetsuyuki Kitamoto; Ryusuke Ae; Tsuyoshi Hamaguchi; Nobuo Sanjo; Tadashi Tsukamoto; Hidehiro Mizusawa; Steven J Collins; Roberto Chiesa; Ignazio Roiter; Jesús de Pedro-Cuesta; Miguel Calero; Michael D Geschwind; Masahito Yamada; Yosikazu Nakamura; Simon Mead

doi:10.1212/WNL.0000000000007745

Age at onset in genetic prion disease and the design of preventive clinical trials

Neurology. 2019 Jul 9;93(2):e125-e134. doi: 10.1212/WNL.0000000000007745. Epub 2019 Jun 6.

Authors

Eric Vallabh Minikel¹, Sonia M Vallabh², Margaret C Orseth², Jean-Philippe Brandel², Stéphane Haïk², Jean-Louis Laplanche², Inga Zerr², Piero Parchi², Sabina Capellari², Jiri Safar², Janna Kenny², Jamie C Fong², Leonel T Takada², Claudia Ponto², Peter Hermann², Tobias Knipper², Christiane Stehmann², Tetsuyuki Kitamoto², Ryusuke Ae², Tsuyoshi Hamaguchi², Nobuo Sanjo², Tadashi Tsukamoto², Hidehiro Mizusawa², Steven J Collins², Roberto Chiesa², Ignazio Roiter², Jesús de Pedro-Cuesta², Miguel Calero², Michael D Geschwind², Masahito Yamada², Yosikazu Nakamura², Simon Mead²

Affiliations

¹ From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK. eminikel@broadinstitute.org.
² From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK.

Abstract

Objective: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.

Methods: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.

Results: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.

Conclusion: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Age of Onset*
Aged
Aged, 80 and over
Child
Clinical Trials as Topic
Female
Genotype
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Mutation
Penetrance
Prion Diseases / genetics
Prion Diseases / prevention & control*
Prion Proteins / genetics
Proportional Hazards Models
Research Design
Young Adult

Substances

PRNP protein, human
Prion Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding