👤 Nicola Specchio

Neuronal ceroid lipofuscinosis type 3 (CLN3) is a rare lysosomal storage disorder characterized by progressive neurodegeneration. No disease-modifying treatments are currently available. Miglustat, a substrate reduction therapy, has shown preclinical efficacy in CLN3 models (conference abstract). The aim of this study was to assess the long-term safety and clinical impact of miglustat in patients with CLN3 disease. This was an open-label, single-center study conducted at Bambino Gesù Children's Hospital in Rome, Italy. Oral miglustat was titrated to 15 mg/kg/d or a maximum of 600 mg/d. Patients were assessed every 6 months using the Unified Batten Disease Rating Scale (UBDRS). The primary outcome was the annual rate of change in the UBDRS physical subscale. Clinical data were analyzed descriptively. Six patients (33% female) with a median age of 20.34 years (interquartile range [IQR] 18.25-23.84) were treated and followed for a median of 3.9 years (IQR 3.32-4.34). The mean annual change in the UBDRS physical score was +1.96 points per year (SD ± 0.80). Miglustat was well tolerated, with only mild, self-limiting gastrointestinal side effects observed. Miglustat showed a favorable safety profile and was associated with a slower rate of physical decline compared with historical controls. Limitations include small sample size, genetic heterogeneity, and open-label design. Show less

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. Show less