Ambroxol in Gaucher disease 3: n-of-1 series

Gaucher disease (GD) is an autosomal recessive lysosomal storage disease (LSD), caused by bi-allelic mutations in GBA1 resulting in a deficiency of the lysosomal enzyme glucocerebrosidase (GCase). GD is biochemically characterized by lysosomal accumulation of glucosylceramide (GL-1) and its deacylated form, glucosylsphinogosine (Lyso-GL1). Clinically, GD is classified intro three subtypes (GD1-3). All present with multisystemic disease manifestations (i.e. enlarged liver and spleen, anaemia). GD2 and GD3 are less common and include involvement of the central nervous system (CNS). GD3 patients present with untreatable progressive neurodegenerative disease, i.e. progressive developmental delay, myoclonic epilepsy, supranuclear gaze palsy and ataxia. The systemic manifestations of GD can be treated by enzyme replacement therapy (ERT). However, ERT is not able to cross the blood-brain barrier (BBB) and hence no treatment for the devastating neurological symptoms is available. Ambroxol is a small molecule chaperone that has been shown to increase GCase activity in vitro and is able to cross the BBB. Because classical randomized controlled trials (RCTs) are unfit to perform due to a low prevalence and heterogeneity of GD3, we will combine the results of several n-of-1 trials. The purpose of this study is to evaluate the neurological efficacy of ambroxol in patients with GD3, using an n-of-1 series.

Based on previous studies, we will expect that ambroxol improves neurological manifestations in patients with GD3.

Outcome measures will be assessed during the baseline period and during the whole trial period every 3 or 6 months. A follow-up visit will be scheduled 6 weeks and 3 months after the end of the trial.

Each patient receives multiple blocks consisting of three time daily ambroxol (25 mg/kg/day) alternated with placebo and washout periods.