ArticleMolecular therapy : the journal of the American Society of Gene Therapy2010
Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 134 citations in OpenAlex.
- Delivery and evaluation of recombinant adeno-associated viral vectors in the equine distal extremity for the treatment of laminitis.Equine veterinary journal · 2017Trial
- Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy.Human gene therapy · 2014Trial
- Environmental and developmental factors shape anti-AAV immunity in pigs.Gene therapy · 2026Article
- High Concordance of Total Antibody and Transduction Inhibition Assays Enables Replacement of Cell-Based Antibody Testing for Preexisting Anti-AAV Immunity in Cynomolgus Monkey.The AAPS journal · 2026Article
- Advancements in CRISPR-basedFrontiers in genome editing · 2026Review
- Metabolic Dysfunction-Associated Steatotic Liver Disease and Emerging Oligonucleotide Therapies.International journal of biological sciences · 2026Review
- 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
- Targeting the Neonatal Fc Receptor in Autoimmune Diseases: Pipeline and Progress.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- Dynamic activation of rAAV transgene expression by a small molecule that recruits endogenous transcriptional machinery.Nucleic acids research · 2025Article
- Prevalence of Neutralizing Antibodies to AAV2 and AAV9 in Individuals with Niemann-Pick Disease, Type C1.Human gene therapy · 2025Article
- Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII.Molecular therapy. Methods & clinical development · 2025Article
- A comprehensive study of AAV tropism across C57BL/6 mice, BALB/c mice, and crab-eating macaques.Molecular therapy. Methods & clinical development · 2025Article
- Review
- Gene therapy in hemophilia: the dawn of a new era.Research and practice in thrombosis and haemostasis · 2025Review
- Identification of a novel neutralization epitope in rhesus AAVs.Molecular therapy. Methods & clinical development · 2024Article
- Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration.Nature biotechnology · 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
- Preexisting antibody assays for gene therapy: Considerations on patient selection cutoffs and companion diagnostic requirements.Molecular therapy. Methods & clinical development · 2024Review
- Article
43 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors.
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Abstract
Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was ~1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.
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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.