The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression

Abstract

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

Morquio‐B disease: Clinical and genetic characteristics of a distinct GLB1‐related dysostosis multiplex

“…Interestingly, six fibroblast lines carried at least one mutation at the amino acid residue Arg-201. Despite significant achievements in preclinical research, with the exception of the aminosugar Miglustat, 66 chaperone therapy yet has not been established for patients with GLB1-related conditions. W273L, the most frequent MBD allele, is not sensitive to chaperon rescue as it encodes for a catalytic mutant within an otherwise stable, normally trafficked and localized protein 12,40,67 (Paschke unpublished).…”

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

“…Interestingly, there have been recent reports (2017) that miglustat may reverse disease progression in juvenile/adult GM1-gangliosidosis, with juvenile patients regaining the ability to walk without assistance for few meters. 73 Although isofagomine generated great interest in clinical trials, it unfortunately did not advance from phase II in 2009, owing to its low in vivo efficacy, which can arise from its high hydrophilicity that compromises pharmacokinetics, namely membrane crossing. The first patents on this molecule expired in 2015.…”

Protein modeling and clinical description of a novel in‐frame GLB1 deletion causing GM1 gangliosidosis type II

“…More recently, injections of adeno‐associated viral vectors (AAV9, AAVrh8) encoding GLB1 have shown success in increasing GLB1 activity, reducing symptoms, and extending lifespan in mice with GM1 gangliosidosis (Deodato et al., ; Weismann et al., ). This form of gene therapy has been extended to larger animal models with promising results paving the way for future clinical trials in humans (Gray‐Edwards et al., ).…”

“…Iminosugar drugs have shown potential in reducing the storage of glycosphingolipids in Glb1-deficient mice, resulting in improved survival (Elliot-Smith et al, 2008;Kasperzyk et al, 2004). The iminosugar Miglustat, which has been approved for the treatment of Gaucher disease type I, was found to reverse disease progression in juvenile/adult GM1 gangliosidosis (Deodato et al, 2017). More recently, injections of adeno-associated viral vectors (AAV9, AAVrh8) encoding GLB1 have shown success in increasing GLB1 activity, reducing symptoms, and extending lifespan in mice with GM1 gangliosidosis (Deodato et al, 2014;Weismann et al, 2015).…”