Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials - 16/04/24

Doi : 10.1016/S1474-4422(24)00099-1

Irene Cortese, MD ^a,⁎ , Gina Norato, MSc ^b, Patrick R Harrington, PhD ^d, Therri Usher, PhD ^e, Ilaria Mainardi, MD ^f, Guillaume Martin-Blondel, MD ^g,^h, Paola Cinque, MD ^f, Eugene O Major, PhD ^c, Virginia Sheikh, MD ^d
^a Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
^b Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
^c Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
^d Division of Antivirals, Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
^e Division of Biometrics IV, Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
^f Unit of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
^g Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
^h Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291—CNRS UMR5051, Université Toulouse III, Toulouse, France

^*Correspondence to: Irene Cortese, Experimental Immunotherapeutics Unit, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USAExperimental Immunotherapeutics UnitNational Institutes of HealthNational Institute of Neurological Disorders and StrokeBethesdaMD20892USA

Summary

Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.

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Plan

Introduction

Pathophysiology and potential biomarkers

Quantitative analyses of JCV DNA copy number in CSF

JCV DNA copy number in CSF as a trial entry criterion

JCV DNA copy number in CSF as a prognostic biomarker for trial stratification

JCV DNA copy number in CSF as a measure or predictor of disease progression and treatment response

Definition of longitudinal metrics for monitoring progressive multifocal leukoencephalopathy response

Decline of JCV DNA in CSF to undetected concentrations

Timing for assessment of quantitative change in JCV DNA concentrations in CSF

Association between specific changes in JCV DNA copy number in CSF and survival

JCV DNA copy number versus progressive multifocal leukoencephalopathy lesion burden on MRI

Conclusions and future directions

Search strategy and selection criteria

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Vol 23 - N° 5

P. 534-544 - mai 2024 Retour au numéro

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Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials - 16/04/24

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