ArticleHuman molecular genetics2014
Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 58 citations in OpenAlex.
- Recent Advances in In Vivo Somatic Cell Gene Modification in Newborn Pups.International journal of molecular sciences · 2023Review
- Intracerebral lentiviral ABCD1 gene therapy in an early disease onset ALD mouse model.Gene therapy · 2023Article
- Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis.Molecular therapy. Methods & clinical development · 2022Article
- Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases.Molecular therapy. Methods & clinical development · 2022Review
- Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.Stem cell reports · 2021Article
- Review
- Canavan Disease as a Model for Gene Therapy-Mediated Myelin Repair.Frontiers in cellular neuroscience · 2021Review
- Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.Frontiers in medicine · 2021Review
- Delivery Platforms for CRISPR/Cas9 Genome Editing of Glial Cells in the Central Nervous System.Frontiers in genome editing · 2021Review
- Article
- Human iPSC-Based Models for the Development of Therapeutics Targeting Neurodegenerative Lysosomal Storage Diseases.Frontiers in molecular biosciences · 2020Review
- Quantitative Microproteomics Based Characterization of the Central and Peripheral Nervous System of a Mouse Model of Krabbe Disease.Molecular & cellular proteomics : MCP · 2019Article
- Adipose Stem Cell Translational Applications: From Bench-to-Bedside.International journal of molecular sciences · 2018Review
- Current Therapeutic Approaches in Leukodystrophies: A Review.Journal of child neurology · 2018Review
- Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I.Journal of inherited metabolic disease · 2017Review
- Gene therapy targeting oligodendrocytes provides therapeutic benefit in a leukodystrophy model.Brain : a journal of neurology · 2017Article
- Two factor-based reprogramming of rodent and human fibroblasts into Schwann cells.Nature communications · 2017Article
- Article
- Generation of Human Induced Pluripotent Stem Cell-Derived Bona Fide Neural Stem Cells for Ex Vivo Gene Therapy of Metachromatic Leukodystrophy.Stem cells translational medicine · 2017Article
- Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30-50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.
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Registered trials
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.