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Genetic strategy to decrease complement activation with adenoviral therapies

Gentile, Christopher M ; Borovjagin, Anton V ; Richter, Jillian R ; Jani, Aditi H ; Wu, Hongju ; Zinn, Kurt R ; Warram, Jason M Ulasov, Ilya

PloS one, 2019-04, Vol.14 (4), p.e0215226-e0215226 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Genetic strategy to decrease complement activation with adenoviral therapies
Autor: Gentile, Christopher M ; Borovjagin, Anton V ; Richter, Jillian R ; Jani, Aditi H ; Wu, Hongju ; Zinn, Kurt R ; Warram, Jason M
Ulasov, Ilya
Assuntos: Adenoviruses ; Adenoviruses, Human - genetics ; Adenoviruses, Human - immunology ; Animals ; Biology and Life Sciences ; Capsid protein ; Capsid Proteins - genetics ; Capsid Proteins - immunology ; Cell Line, Tumor ; Complement ; Complement activation ; Complement Activation - genetics ; Composition ; Disease Models, Animal ; Expression vectors ; Fireflies ; Gene editing ; Gene therapy ; Genes ; Genetic aspects ; Genetic modification ; Genetic Therapy - adverse effects ; Genetic Therapy - methods ; Genetic vectors ; Genetic Vectors - administration & dosage ; Genetic Vectors - adverse effects ; Genetic Vectors - genetics ; Hepatocytes ; Histidine ; Human performance ; Humans ; Immune response ; Immune response (humoral) ; Immunity, Humoral - immunology ; Infectivity ; Injections, Intralesional ; Innate immunity ; Liver ; Liver - cytology ; Liver - immunology ; Luciferase ; Male ; Medicine and Health Sciences ; Methods ; Mice ; Neoplasms - immunology ; Neoplasms - therapy ; Otolaryngology ; Peptides ; Peptides - genetics ; Proteins ; Research and Analysis Methods ; Transduction, Genetic ; Tropism ; Tumors ; Vectors (Biology) ; Viral proteins
É parte de: PloS one, 2019-04, Vol.14 (4), p.e0215226-e0215226
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Competing Interests: The authors have declared that no competing interests exist.
Descrição: A 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. A 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. In 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. Displaying 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Genetic strategy to decrease complement activation with adenoviral therapies

Gentile, Christopher M ; Borovjagin, Anton V ; Richter, Jillian R ; Jani, Aditi H ; Wu, Hongju ; Zinn, Kurt R ; Warram, Jason M Ulasov, Ilya

United States: Public Library of Science

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