ArticleEuropean journal of human genetics : EJHG2010
Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses.
Article in European journal of human genetics : EJHG, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 45 citations in OpenAlex.
- Systematic Review of Genetic Substrate Reduction Therapy in Lysosomal Storage Diseases: Opportunities, Challenges and Delivery Systems.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Pooled it
- Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: assessment of effects on cognitive functions and general status of patients.Medical science monitor : international medical journal of experimental and clinical research · 2011Trial
- Inhibition of heparan sulfate synthesis by resveratrol in mucopolysaccharidosis type I and IIIB.Metabolic brain disease · 2026Article
- mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis.International journal of molecular sciences · 2025Article
- MPSI Manifestations and Treatment Outcome: Skeletal Focus.International journal of molecular sciences · 2022Review
- Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease.American journal of physiology. Cell physiology · 2022Review
- Opportunities and challenges for antisense oligonucleotide therapies.Journal of inherited metabolic disease · 2021Review
- Mucopolysaccharidosis III: Molecular basis and treatment.Pediatric endocrinology, diabetes, and metabolism · 2021Review
- Novel therapies for mucopolysaccharidosis type III.Journal of inherited metabolic disease · 2021Review
- Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches.International journal of molecular sciences · 2020Review
- Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach.International journal of molecular sciences · 2020Review
- The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination.Journal of neuroinflammation · 2020Article
- Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development.Journal of clinical medicine · 2020Article
- A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise.Medical research archives · 2020Article
- Substrate reduction therapy for inborn errors of metabolism.Emerging topics in life sciences · 2019Article
- How close are we to therapies for Sanfilippo disease?Metabolic brain disease · 2018Review
- Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.American journal of human genetics · 2017Article
- Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders.Diseases (Basel, Switzerland) · 2016Review
- EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome.Scientific reports · 2015Article
- Heparan sulfate biosynthesis: regulation and variability.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2012Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurological pathology is characteristic of the mucopolysaccharidoses (MPSs) that store heparan sulphate (HS) glycosaminoglycan (gag) and has been proven to be refractory to systemic therapies. Substrate deprivation therapy (SDT) using general inhibitors of gag synthesis improves neurological function in mouse models of MPS, but is not specific to an MPS type. We have investigated RNA interference (RNAi) as a method of targeting SDT to the HS synthesising enzymes, EXTL2 and EXTL3. Multiple shRNA molecules specific to EXTL2 or EXTL3 were designed and validated in a reporter gene assay, with four out of six shRNA constructs reducing expression by over 90%. The three EXTL2-specific shRNA constructs reduced endogenous target gene expression by 68, 32 and 65%, and decreased gag synthesis by 46, 50 and 27%. One EXTL3-specific shRNA construct reduced endogenous target gene expression by 14% and gag synthesis by 39%. Lysosomal gag levels in MPS IIIA and MPS I fibroblasts were also reduced by EXTL2 and EXTL3-specific shRNA. Incorporation of shRNAs into a lentiviral expression system reduced gene expression, and one EXTL2-specific shRNA reduced gag synthesis. These results indicate that deprivation therapy through shRNA-mediated RNAi has potential as a therapy for HS-storing MPSs.
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