Pharmacological chaperone and substrate reduction therapy for neuropathic Gaucher disease: ambroxol and venglustat for GBA1 c.1342G>C (p.Asp448His)

For GBA1 c.1342G>C (p.Asp448His), a pathogenic missense variant that produces a misfolded but catalytically competent glucocerebrosidase (GCase), pharmacological chaperone therapy (PCT) with ambroxol and substrate reduction therapy (SRT) with venglustat represent mechanistically distinct small-molecule strategies that can cross the blood-brain barrier — a critical advantage over intravenous enzyme replacement therapy (ERT, which cannot treat the neurological component). The p.Asp448His substitution (historically D409H) is associated with severe type 3 (chronic neuropathic) Gaucher disease and the rare cardiovascular subtype with aortic/mitral valve calcification.

Ambroxol is a pH-dependent pharmacological chaperone that binds to and stabilizes GCase in the endoplasmic reticulum, promoting proper folding and lysosomal trafficking. It crosses the BBB and has shown GCase activity increases in GBA1-mutant fibroblasts and Gaucher patient-derived neurons. Narita et al. (Ann Neurol 2016; PMID:27389578) conducted an open-label pilot study of high-dose oral ambroxol in neuropathic Gaucher patients, showing increased lymphocyte GCase activity and CSF GCase levels, with stabilization of neurological symptoms in some patients. Importantly, ambroxol is most effective for missense variants that produce misfolded protein (like p.Asp448His) rather than null variants that produce no protein. Venglustat (Ibiglustat, Sanofi) is a brain-penetrant glucosylceramide synthase inhibitor that reduces substrate accumulation upstream of GCase. The LEAP Phase 2 trial (NCT02843035) in GBA1-associated Parkinson disease provided proof-of-concept for CNS target engagement, though efficacy results were mixed. For Gaucher type 3, substrate reduction could complement residual GCase activity to bring glucosylceramide levels below pathogenic thresholds.

Pharmacological chaperone therapy is mutation-dependent: ambroxol stabilizes misfolded GCase that retains some structural integrity, so it works best for specific missense variants. For the perinatal-lethal form associated with p.Asp448His in homozygosity or compound heterozygosity with null alleles, the residual GCase may be too low for chaperone rescue to achieve clinically meaningful activity. Venglustat's mixed Phase 2 results in GBA-Parkinson (MOVES-PD trial did not meet primary endpoint) raise questions about SRT efficacy in established neurodegeneration. The perinatal-lethal form is typically fatal within months, leaving almost no time for oral small-molecule therapy to accumulate sufficient CNS effect. Neither ambroxol nor venglustat has been studied in controlled trials specifically for neuropathic Gaucher disease in infants. ERT (imiglucerase, velaglucerase) remains essential for managing visceral disease (hepatosplenomegaly, cytopenias) but does not address CNS pathology. The p.Asp448His variant's association with the cardiovascular subtype adds further complexity not addressed by any current therapy.