Cited by 10Virus-based gene therapy researchRNA Interference and Gene DeliveryImmunotherapy and Immune Responses

Synergistic inhibition of PARP-1 and NF-κB signaling downregulates immune response against recombinant AAV2 vectors during hepatic gene therapy

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Hareendran, Sangeetha, Ramakrishna, Banumathi, Jayandharan, Giridhara R.·2016·European Journal of Immunology

Abstract

Host immune response remains a key obstacle to widespread application of adeno‐associated virus (AAV) based gene therapy. Thus, targeted inhibition of the signaling pathways that trigger such immune responses will be beneficial. Previous studies have reported that DNA damage response proteins such as poly(ADP‐ribose) polymerase‐1 (PARP‐1) negatively affect the integration of AAV in the host genome. However, the role of PARP‐1 in regulating AAV transduction and the immune response against these vectors has not been elucidated. In this study, we demonstrate that repression of PARP‐1 improves the transduction of single‐stranded AAV vectors both in vitro (∼174%) and in vivo (two‐ to 3.4‐fold). Inhibition of PARP‐1, also significantly downregulated the expression of several proinflammatory and cytokine markers such as TLRs, ILs, NF‐κB subunit proteins associated with the host innate response against self‐complementary AAV2 vectors. The suppression of the inflammatory response targeted against these vectors was more effective upon combined inhibition of PARP‐1 and NF‐κB signaling. This strategy also effectively attenuated the AAV capsid‐specific cytotoxic T‐cell response, with minimal effect on vector transduction, as demonstrated in normal C57BL/6 and hemophilia B mice. These data suggest that targeting specific host cellular proteins could be useful to attenuate the immune barriers to AAV‐mediated gene therapy.

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  • PARP-1 inhibition can attenuate the AAV capsid-directed cytotoxic T cell response, downregulate TLR and NF-kB expression, and improve the transduction efficiency of AAV vectors by three-fold in the liver.

    “Moreover, PARP-1 inhibition can attenuate the AAV capsid-directed cytotoxic T cell response, downregulate TLR and NF-kB expression, and improve the transduction efficiency of AAV vectors by three-fold in the liver (Hareendran et al., 2016).”

    From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Hareendran et al., 2016

    The Discussion reports that PARP-1 inhibition downregulated TLRs and NF-κB-related inflammatory factors. The transduction-results section reports increased liver expression in mice, but the increase was about 3.4-fold for ssAAV8 and twofold for ssAAV2, not threefold for AAV vectors generally. The cytotoxic T-cell-results section attributes the reduced capsid-specific response to combined PARP-1 and NF-κB inhibition, not PARP-1 inhibition alone. (LLM, conf=0.90)

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Research works printed but not linked: 2

  1. C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 15214141, 2016, 1, · DOI
  2. C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 15214141, 2016, 1, · DOI

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Authors
Hareendran, S., Ramakrishna, B., & Jayandharan, G. R.
Affiliations
Christian Medical College, Vellore (IN)
Corresponding author
Jayandharan, Giridhara R.
Venue
European Journal of Immunology
Publisher
Wiley
Published
2015-11-05
Volume
46
Issue
1
Pages
154-166
ISSN
  • 0014-2980 (ISSN-L)
  • 1521-4141
OpenAlex
W1946287926
Cited by
10
References
68
Citations by year
2025: 2 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 1
FWCI
0.46
Type
journal article
Language
en
Open access
Locations
  • European Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Department of Biotechnology, Ministry of Science and Technology, India (BT/03/IYBA/2010, IYBA/2010)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
PARP1, NF-κB signaling, adeno-associated virus type 2, AAV gene therapy, host immune response, hepatic gene therapy, AAV transduction, innate immunity, TLRs, cytokines, cytotoxic T lymphocytes, hemophilia B, DNA damage response
MeSH terms
Poly (ADP-Ribose) Polymerase-1, Dependovirus, Animals, Hemophilia B, Disease Models, Animal, Drug Synergism, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Genetic Vectors, HeLa Cells, Humans, Liver, Mice, Inbred BALB C, Mice, Inbred C57BL, Poly(ADP-ribose) Polymerases, Transduction, Genetic, Transfection, Blotting, Western, Genetic Therapy, Down-Regulation, NF-kappa B, Mice, Real-Time Polymerase Chain Reaction

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