ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Review
- Article
- Maximising opportunity for therapeutic success: sequential participation in cystic fibrosis nucleic acid-based therapy trials.The Lancet. Respiratory medicine · 2025Review
- Investigating the Cellular Effects of GALC Dosing in Enzyme Replacement Therapy for Krabbe Disease Supports the Role of Nanomedicine.Advanced biology · 2025Article
- Restoring brain barriers: an innovative approach for treating neurological disorders.Fluids and barriers of the CNS · 2025Review
- Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.Journal of neuroimmunology · 2025Review
- Gene therapy ameliorates bowel dysmotility and enteric neuron degeneration and extends survival in lysosomal storage disorder mouse models.Science translational medicine · 2025Article
- Advances in AAV-mediated gene replacement therapy for pediatric monogenic neurological disorders.Molecular therapy. Methods & clinical development · 2024Review
- Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Article
- Untargeted Lipidomic Approach for Studying Different Nervous System Tissues of the Murine Model of Krabbe Disease.Biomolecules · 2023Article
- AAV-based in vivo gene therapy for neurological disorders.Nature reviews. Drug discovery · 2023Review
- CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy.The Journal of experimental medicine · 2023Article
- Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease.Frontiers in molecular neuroscience · 2023Article
- Globoid Cell Leukodystrophy (Krabbe Disease): An Update.ImmunoTargets and therapy · 2023Review
- Neurodegenerative Disorder Risk in Krabbe Disease Carriers.International journal of molecular sciences · 2022Article
- Non-Viral Delivery of RNA Gene Therapy to the Central Nervous System.Pharmaceutics · 2022Review
- Chronic lithium administration in a mouse model for Krabbe disease.JIMD reports · 2022Article
- AAV-CNS matters turn from gray to white.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
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15 authors at 6 institutions in 1 country.
Funding
Abstract
Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. Extravasation of fibrinogen correlated with tight junction disruptions of the vasculature within the lesioned areas. The lesions were surrounded by normal appearing white matter. Our study shows that the dysregulation of therapeutic GALC was likely driven by the exhaustion of therapeutic AAV episomal DNA within the lesions, paralleling the presence of proliferating oligodendrocyte progenitors and glia. We believe that this is the first demonstration of diminishing expression in vivo from an AAV gene therapy vector with detrimental effects in the brain of a lysosomal storage disease animal model. The development of this phenotype linking localized loss of GALC activity with relapsing neuropathology in the adult brain of neonatally AAV-gene therapy-treated Twitcher mice identifies and alerts to possible late-onset reductions of AAV efficacy, with implications to other genetic leukodystrophies.
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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.