ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Enhanced Efficacy and Increased Long-Term Toxicity of CNS-Directed, AAV-Based Combination Therapy for 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 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.Frontiers in immunology · 2022Pooled it
- Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice.Nature communications · 2026Article
- Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease.iScience · 2026Article
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- Stem cell and gene therapies for leukodystrophies.Molecular therapy. Methods & clinical development · 2025Review
- Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.Immunity · 2025Article
- Delivery of genetic medicines for muscular dystrophies.Cell reports. Medicine · 2025Review
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- Lipid nanoparticle technology-mediated therapeutic gene manipulation in the eyes.Molecular therapy. Nucleic acids · 2024Review
- Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease.bioRxiv : the preprint server for biology · 2024Article
- Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models.Molecular therapy. Methods & clinical development · 2024Article
- Article
- A novel variant of GALC in a familial case of Krabbe disease: Insights from structural bioinformatics and molecular dynamics simulation.Genes & diseases · 2023Article
- AAV-based in vivo gene therapy for neurological disorders.Nature reviews. Drug discovery · 2023Review
- 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
- Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- Transient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice.Nature communications · 2022Article
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13 authors at 3 institutions in 1 country.
Funding
Abstract
Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials.
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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.