ArticleThe Journal of clinical investigation2020
Krabbe disease successfully treated via monotherapy of intrathecal gene therapy.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 67 citations in OpenAlex.
- Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis.Frontiers in immunology · 2026Pooled it
- Schwann Cell-Specific ATG7-Dependent Autophagy Protects Myelin in a Mouse Model of Krabbe Disease.Glia · 2026Article
- Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice.Life science alliance · 2026Article
- Review
- Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease.iScience · 2026Article
- Molecular Dynamics Simulations of 4Computational and structural biotechnology journal · 2026Article
- Comparative analysis of cell-specific promoters in AAV9-mediated gene therapy targeting the central nervous system.Molecular therapy. Methods & clinical development · 2025Article
- Genetic and Clinical Characteristics of Chinese Adult Patients With Krabbe Disease.CNS neuroscience & therapeutics · 2025Article
- Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.Molecular therapy. Methods & clinical development · 2025Article
- Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.Journal of neuroimmunology · 2025Review
- Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.Immunity · 2025Article
- Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Manifestations of systemic disease in the retina and fundus of cats and dogs.Frontiers in veterinary science · 2024Review
- AAV-based in vivo gene therapy for neurological disorders.Nature reviews. Drug discovery · 2023Review
- Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis.International journal of molecular sciences · 2023Article
- Identifying altered developmental pathways in human globoid cell leukodystrophy iPSCs-derived NSCs using transcriptome profiling.BMC genomics · 2023Article
- Review
- 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
- Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery.Molecular therapy. Methods & clinical development · 2022Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 1 country.
Funding
Abstract
Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically.
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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.