ArticleHepatology (Baltimore, Md.)2017
Autophagy determines efficiency of liver-directed gene therapy with adeno-associated viral vectors.
Article in Hepatology (Baltimore, Md.), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 46 citations in OpenAlex.
- Defining the safety and efficacy of liver-directed AAV gene therapy using a human liver tissue-equivalent platform.Molecular therapy. Advances · 2026Article
- AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.Nature biotechnology · 2025Article
- Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes.Nature communications · 2025Article
- Identification of the role of SNARE proteins in rAAV vector production through interaction with the viral MAAP.Molecular therapy. Methods & clinical development · 2025Article
- Role of FoxP3Human gene therapy · 2024Review
- Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver.JCI insight · 2024Article
- Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice.Molecular therapy. Methods & clinical development · 2022Article
- IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- The Emerging Role of Extracellular Vesicles and Autophagy Machinery in NASH-Future Horizons in NASH Management.International journal of molecular sciences · 2022Review
- Review
- Fludarabine increases nuclease-free AAV- and CRISPR/Cas9-mediated homologous recombination in mice.Nature biotechnology · 2022Article
- Benefits of therapy by dynamin-2-mutant-specific silencing are maintained with time in a mouse model of dominant centronuclear myopathy.Molecular therapy. Nucleic acids · 2022Article
- Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors.Cancers · 2022Article
- Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.PloS one · 2022Article
- ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia.Molecular therapy. Methods & clinical development · 2021Article
- Efficacy of AAV8-hMolecular therapy. Methods & clinical development · 2021Article
- Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders.EMBO molecular medicine · 2021Article
- Enhancement of liver-directed transgene expression at initial and repeat doses of AAV vectors admixed with ImmTOR nanoparticles.Science advances · 2021Article
- Combined Treatment with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer-PPMO and AAV-U7 Rescues the Severe DMD Phenotype in Mice.Molecular therapy. Methods & clinical development · 2020Article
- Review
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18 authors at 8 institutions in 3 countries.
Funding
Abstract
Use of adeno-associated viral (AAV) vectors for liver-directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)-dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV-mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short-term treatment with a single dose of torin 1 significantly increased vector-mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid-α-glucosidase in nonhuman primates.
conclusionWe identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver-directed gene therapy using AAV vectors and showed in a proof-of-principle study how this virus-host interaction can be employed to enhance efficacy of this vector system. (Hepatology 2017;66:252-265).
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