Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing
- 1Third Department of Pediatrics, Center of Postgraduate Medical Education, 05-092 Dziekanów Leśny, Poland
- 2Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Abstract
Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood–brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann–Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay–Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
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BibTeX
@article{lipinski2026miglustat,
title = {{Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing}},
author = {Patryk Lipiński and Grzegorz Węgrzyn},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188336},
url = {https://www.mdpi.com/1422-0067/27/18/8336},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing
AU - Patryk Lipiński
AU - Grzegorz Węgrzyn
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188336
UR - https://www.mdpi.com/1422-0067/27/18/8336
AB - Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood–brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann–Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay–Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
SN - 1422-0067
ER -