ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 34 citations in OpenAlex.
- A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.Haemophilia : the official journal of the World Federation of Hemophilia · 2025Trial
- An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.Cell chemical biology · 2026Article
- Factor VIII originates primarily from anatomically distinct subsets of liver sinusoidal endothelial cells.Blood advances · 2026Article
- Identification of alterations of immunometabolism associated with Pompe disease.Cellular and molecular life sciences : CMLS · 2026Article
- Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders.Journal of blood medicine · 2026Review
- Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression.Therapeutic advances in hematology · 2026Review
- Review
- AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.Nature biotechnology · 2025Article
- Gene therapy for hemophilia - From basic science to first approvals of "one-and-done" therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer.Communications medicine · 2025Article
- Optimizing liver health before and after gene therapy for hemophilia A.Blood advances · 2024Review
- Roctavian gene therapy for hemophilia A.Blood advances · 2024Review
- Viral Vector Based Immunotherapy for Peanut Allergy.Viruses · 2024Review
- Role of FoxP3Human gene therapy · 2024Review
- Innate Immune Sensing of Adeno-Associated Virus Vectors.Human gene therapy · 2024Review
- Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver.JCI insight · 2024Article
- B cell focused transient immune suppression protocol for efficient AAV readministration to the liver.Molecular therapy. Methods & clinical development · 2024Article
- TLR9-independent CD8Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Cellular stress and coagulation factor production: when more is not necessarily better.Journal of thrombosis and haemostasis : JTH · 2023Review
- Accessorizing viral vectors with extracellular vesicles for enhanced performance.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
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Authors and funding
17 authors at 5 institutions in 1 country.
Funding
Abstract
Hepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8
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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.