Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study

Area of Science:

• Biochemistry
• Neurology
• Pharmacology

Background:

• Gaucher disease (GD) is a lysosomal storage disorder resulting from glucocerebrosidase deficiency.
• Current therapies offer limited efficacy for neurological manifestations of GD.
• Pharmacological chaperone therapy presents a novel treatment strategy for neuronopathic GD.

Purpose of the Study:

• To evaluate the safety and tolerability of high-dose oral ambroxol in patients with neuronopathic Gaucher disease.
• To assess the neurological efficacy of ambroxol as a pharmacological chaperone.
• To investigate ambroxol's ability to cross the blood-brain barrier and impact disease biomarkers.

Main Methods:

• An open-label pilot study involving five patients with neuronopathic GD receiving high-dose oral ambroxol and enzyme replacement therapy.
• Safety assessments included adverse events, physical examinations, ECGs, lab studies, and drug concentrations.
• Efficacy was measured by changes in lymphocyte glucocerebrosidase activity, cerebrospinal fluid glucosylsphingosine levels, and various neurological assessments.

Main Results:

• High-dose oral ambroxol demonstrated good safety and tolerability.
• Significant increases in lymphocyte glucocerebrosidase activity and decreased CSF glucosylsphingosine levels were observed.
• Marked improvements in myoclonus, seizures, and pupillary light reflex dysfunction occurred in all patients, with two regaining ambulation.

Conclusions:

• High-dose oral ambroxol shows potential as a pharmacological chaperone therapy for neuronopathic Gaucher disease.
• Ambroxol's ability to penetrate the blood-brain barrier and improve neurological symptoms is promising.
• Further clinical trials are warranted to confirm these findings and establish ambroxol's therapeutic role.