Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study

Abstract

ObjectiveGaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.MethodsThis open‐label pilot study included five patients who received high‐dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies.ResultsHigh‐dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood–brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again.InterpretationPharmacological chaperone therapy with high‐dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

Exploring genetic modifiers of Gaucher disease: The next horizon

“…While recombinant GCase administration restored the number of lysosomes, this effect was enhanced when TFEB was overexpressed (Awad et al., ). The purported pharmacological chaperone ambroxol was shown to increase the expression of TFEB, as well as several lysosomal genes including GCase (McNeill et al., ; Narita et al., ).…”

Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder

“…Chaperones can cross the blood-brain barrier and selectively bind to misfolded glucocerebrosidases facilitating the correction of protein misfolding and improving enzyme function. A recent pilot study investigating the efficacy of PCT in patients with Type III GD reported marked improvements in saccadic initiation latency and pupillary light reflex dysfunction107 using chromatic pupillometry device 108. Future studies should evaluate the efficacy of PCT in treating ophthalmic manifestations of GD.…”

The Complicated Relationship between Gaucher Disease and Parkinsonism: Insights from a Rare Disease

“…The potency of ambroxol for GD has been demonstrated in various in vitro and in vivo models such as cells, mice, and flies (Luan et al, 2013; Maor et al, 2016). Pilot studies conducted in 12 patients with GD type 1 and five with neuronopathic GD demonstrated no further deterioration of clinical symptoms in the patients with GD type 1 and improvement of myoclonus and pupillary light reflex in patients with GD type 3 (Narita et al, 2016; Zimran et al, 2013). In an in vitro study where α-syn was reduced in an ambroxol-treated α-syn over-expressing neuroblastoma cell line and preliminary reports of the efficacy of ambroxol in neuronopathic GD, support further study of this molecule (McNeill et al, 2014).…”