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Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy

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Abstract

Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.

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Acknowledgements

English text editing was provided by Dr. David Macari. Paolo Curatolo participated in the EPISTOP study (https://www.epistop.eu) funded under the European Community's 7th Framework Program under Grant Agreement no. 602391

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Authors and Affiliations

  1. Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165, Rome, Italy

    Nicola Specchio, Alessandro Ferretti, Marina Trivisano, Nicola Pietrafusa, Chiara Pepi & Costanza Calabrese

  2. Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy

    Chiara Pepi & Paolo Curatolo

  3. Clinical Trial Unit, University Department of Paediatrics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Susanna Livadiotti & Alessandra Simonetti

  4. University Department of Paediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Paolo Rossi

  5. Department of Medicine, Chair of Paediatrics, University of Rome ‘‘Tor Vergata’’, Rome, Italy

    Paolo Rossi

  6. Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy

    Federico Vigevano

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  1. Nicola Specchio
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Correspondence to Nicola Specchio.

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NS has received support from Biomarin, and Amicus, and has served as a paid consultant for Livanova, Biomarin; PC has served as a paid consultant for Novartis; FV has served as paid consultant for Zogenix, Eisai, GW Pharma, Biomarin; MT has served as paid consultant for Biomarin; all other authors report no conflict of interest.

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NS and AF made substantial contributions to the conception and design of the work; and the acquisition, analysis, and interpretation of data and drafted the work; MT, NP, CP, CC, AS made substantial contributions to the conception and design of the work; and the acquisition, analysis, and interpretation of data; MT, SL, PR, PC revised the manuscript critically for important intellectual content; FV revised the manuscript critically for important intellectual content and acted as senior coordinator of the work. All authors approved the version to be published.

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Specchio, N., Ferretti, A., Trivisano, M. et al. Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy. Drugs 81, 101–123 (2021). https://doi.org/10.1007/s40265-020-01440-7

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