ArticleThe FEBS journal2010
The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase.
Article in The FEBS journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 158 citations in OpenAlex.
- An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).Molecular genetics and metabolism · 2011Trial
- Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB.Biomolecules · 2026Article
- Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.Frontiers in neuroscience · 2026Review
- Current opinion on pluripotent stem cell technology in Gaucher's disease: challenges and future prospects.Cytotechnology · 2025Review
- Review
- A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.Communications chemistry · 2024Article
- Animal Models for the Study of Gaucher Disease.International journal of molecular sciences · 2023Review
- Autophagy: Regulator of cell death.Cell death & disease · 2023Review
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Therapeutic Role of Pharmacological Chaperones in Lysosomal Storage Disorders: A Review of the Evidence and Informed Approach to Reclassification.Biomolecules · 2023Review
- Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases.IBRO neuroscience reports · 2023Article
- High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy.International journal of molecular sciences · 2023Article
- Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology.International journal of molecular sciences · 2023Review
- Precision Medicine in Parkinson's Disease: From Genetic Risk Signals to Personalized Therapy.Brain sciences · 2022Review
- Review
- Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol.International journal of molecular sciences · 2022Article
- Glucocerebrosidase Mutations Cause Mitochondrial and Lysosomal Dysfunction in Parkinson's Disease: Pathogenesis and Therapeutic Implications.Frontiers in aging neuroscience · 2022Review
- Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues.Nature communications · 2021Article
- Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques.International journal of molecular sciences · 2021Article
- Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.International journal of molecular sciences · 2021Review
15 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 3 institutions in 3 countries.
Funding
Abstract
Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid beta-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5- and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2- to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.