ArticleThe Journal of clinical investigation2016
Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 31 citations in OpenAlex.
- AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.Cell reports. Medicine · 2026Article
- N-glycan-modified α-L-iduronidase produced by transgenic silkworms ameliorates clinical signs in a Japanese macaque with mucopolysaccharidosis I.Communications medicine · 2025Article
- Intracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.PloS one · 2025Article
- Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.Molecular therapy. Methods & clinical development · 2024Article
- Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.Nature cell biology · 2024Article
- α-Mannosidase and β-D-N-acetylhexosaminidase outside the wall: partner exoglycosidases involved in fruit ripening process.Plant molecular biology · 2023Review
- Reversal of neuroinflammation in novel GS model mice by single i.c.v. administration of CHO-derived rhCTSA precursor protein.Molecular therapy. Methods & clinical development · 2022Article
- Increased phosphorylation of HexM improves lysosomal uptake and potential for managing GM2 gangliosidoses.BBA advances · 2022Article
- Mass Spectrometry Imaging for Glycome in the Brain.Frontiers in neuroanatomy · 2021Review
- Brain endothelial specific gene therapy improves experimental Sandhoff disease.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2020Article
- Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure.Biochimica et biophysica acta. Proteins and proteomics · 2017Article
- Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease.Molecular therapy. Methods & clinical development · 2017Article
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of β-hexosaminidase A, which comprises an αβ heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring β-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit β (HexB), which we have termed mod2B, composed of homodimeric β subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside-degrading activity and protease resistance. We also developed fluorescent probes that allow visualization of endocytosis of mod2B via mannose 6-phosphate receptors and delivery of mod2B to lysosomes in GM2 gangliosidosis models. In addition, we applied imaging mass spectrometry to monitor efficacy of this approach in Sandhoff disease model mice. Following i.c.v. administration, mod2B was widely distributed and reduced accumulation of GM2, asialo-GM2, and bis(monoacylglycero)phosphate in brain regions including the hypothalamus, hippocampus, and cerebellum. Moreover, mod2B administration markedly improved motor dysfunction and a prolonged lifespan in Sandhoff disease mice. Together, the results of our study indicate that mod2B has potential for intracerebrospinal fluid enzyme replacement therapy and should be further explored as a gene therapy for GM2 gangliosidoses.
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