ArticleMolecular therapy : the journal of the American Society of Gene Therapy2011
Systemic administration of AAV8-α-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 54 citations in OpenAlex.
- Liver-specific gene therapy based on self-complementary adeno-associated virus for lysosomal acid lipase deficiency.Frontiers in pharmacology · 2026Article
- Review
- FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease type 1.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Reversing Pathology in an Aggravated Fabry Mouse Model Using Low-Dose Engineered Human Alpha-Galactosidase A AAV Gene Therapy.Biomedicines · 2025Article
- Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease.Molecular therapy. Methods & clinical development · 2024Article
- Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human factor IX variant in mice and rhesus macaques.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Recombinant adeno-associated virus 8 vector in gene therapy: Opportunities and challenges.Genes & diseases · 2024Review
- Liver directed adeno-associated viral vectors to treat metabolic disease.Journal of inherited metabolic disease · 2024Review
- Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease.Orphanet journal of rare diseases · 2023Article
- Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease.Gene therapy · 2023Article
- Safety of Intravenous Administration of an AAV8 Vector Coding for an Oxidation-Resistant Human α1-Antitrypsin for the Treatment of α1-Antitrypsin Deficiency.Human gene therapy · 2023Article
- Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS).Leukemia · 2022Article
- Chimeric Mice Engrafted With Canine Hepatocytes Exhibits Similar AAV Transduction Efficiency to Hemophilia B Dog.Frontiers in pharmacology · 2022Article
- Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A.Molecular therapy. Methods & clinical development · 2021Article
- AAV2/6 Gene Therapy in a Murine Model of Fabry Disease Results in Supraphysiological Enzyme Activity and Effective Substrate Reduction.Molecular therapy. Methods & clinical development · 2020Article
- Immune Response Mechanisms against AAV Vectors in Animal Models.Molecular therapy. Methods & clinical development · 2020Review
- Engineering adeno-associated virus vectors for gene therapy.Nature reviews. Genetics · 2020Review
- Superior human hepatocyte transduction with adeno-associated virus vector serotype 7.Gene therapy · 2019Article
- Article
- Complexity of immune responses to AAV transgene products - Example of factor IX.Cellular immunology · 2019Review
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding α-galactosidase A (α-gal). As in mice, sustained expression in monkeys attenuated antibody responses to α-gal. However, this effect was not robust, and sustained α-gal levels were 1-2 logs lower than those achieved in male mice at the same vector dose. Because our mouse studies had shown that antibody levels were directly related to expression levels, several strategies were evaluated to increase expression in monkeys. Unlike mice, expression in monkeys did not respond to androgens. Local delivery to the liver, immune suppression, a self-complementary vector and pharmacologic approaches similarly failed to increase expression. While equivalent vector copies reached mouse and primate liver and there were no apparent differences in vector form, methylation or deamination, transgene expression was limited at the mRNA level in monkeys. These results suggest that compared to mice, transcription from an AAV8 vector in monkeys can be significantly reduced. They also suggest some current limits on achieving clinically useful antibody reduction and therapeutic benefit for lysosomal storage diseases using a systemic AAV8-based approach.
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