ArticlePloS one2019
Genetic strategy to decrease complement activation with adenoviral therapies.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 5 citations in OpenAlex.
- Reprogramming innate immunity through viral interference: A double-edged strategy for enhancing and containing gene therapies.Molecular therapy. Nucleic acids · 2026Review
- Innate Immune Response to Viral Vectors in Gene Therapy.Viruses · 2023Review
- Emerging roles of the complement system in host-pathogen interactions.Trends in microbiology · 2022Review
- Delivery of Anti-IFNAR1 shRNA to Hepatic Cells Decreases IFNAR1 Gene Expression and Improves Adenoviral Transduction and Transgene Expression.Molecular biotechnology · 2022Article
- Current strategies to circumvent the antiviral immunity to optimize cancer virotherapy.Journal for immunotherapy of cancer · 2021Review
- Retargeting adenoviruses for therapeutic applications and vaccines.FEBS letters · 2020Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundA major obstacle to using recombinant adenoviral vectors in gene therapy is the natural ability of human adenovirus to activate the classical and alternate complement pathways. These innate immune responses contribute to hepatic adenoviral uptake following systemic delivery and enhance the humoral immune responses associated with adenoviral infection.
methodsA recombinant Ad5 vector was genetically modified to display a peptide sequence ("rH17d'"), a known inhibitor of the classical complement pathway. The replication-defective vectors Ad5.HVR2-rH17d' and Ad5.HVR5-rH17d' were constructed by engineering the rH17d' peptide into the hypervariable region (HVR)-2 or HVR5 of their major capsid protein hexon. Control Ad5 vectors were created by incorporation of a 6-histidine (His6)-insert in either HVR2 or HVR5 (Ad5.HVR2-His6 and Ad5.HVR5-His6, respectively). All vectors encoded CMV promoter-controlled firefly luciferase (Luc). The four vectors were evaluated in TIB76 mouse liver cells and immunocompetent mice to compare infectivity and liver sequestration, respectively.
resultsIn vitro studies demonstrated that preincubation of all the Ad5 vectors with fresh serum significantly increased their gene transfer relative to preincubation with PBS except Ad5.HVR5-rH17d', whose infectivity of liver cells showed no serum-mediated enhancement. In line with that, mice injected with Ad5.HVR2-rH17d' or Ad5.HVR5-rH17d' showed significantly lower luciferase expression levels in the liver as compared to the respective control vectors, whereas efficiency of tumor transduction by rH17d' and His6 vectors following their intratumoral injection was similar.
conclusionsDisplaying a complement-inhibiting peptide on the Ad5 capsid surface by genetic modification of the hexon protein could be a suitable strategy for reducing Ad5 liver tropism (Ad5 sequestration by liver), which may be applicable to other gene therapy vectors with natural liver tropism.
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