Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy
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REVIEW ARTICLE
Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy Nicola Specchio1 · Alessandro Ferretti1 · Marina Trivisano1 · Nicola Pietrafusa1 · Chiara Pepi1,2 · Costanza Calabrese1 · Susanna Livadiotti3 · Alessandra Simonetti3 · Paolo Rossi4,5 · Paolo Curatolo2 · Federico Vigevano6
© Springer Nature Switzerland AG 2020
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.
1 Introduction
* Nicola Specchio [email protected] 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
2
Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
3
Clinical Trial Unit, University Department of Paediatrics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
4
University Department of Paediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
5
Department of Medicine, Chair of Paediatrics, University of Rome ‘‘Tor Vergata’’, Rome, Italy
6
Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
Neuronal ceroid lipofuscinosis (NCL) is a group of degenerative genetic diseases that together form the most common cause of dementia in Querychildren [1–4]. Cardinal to NCL pathology is the toxic levels of protein aggregates in the central nervous system (CNS) [5, 6], which more specifically
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