Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas

Nault, Jean–Charles; Datta, Shalini; Imbeaud, Sandrine; Franconi, Andrea; Mallet, Maxime; Couchy, Gabrielle; Letouzé, Éric; Pilati, Camilla; Verret, Benjamin; Blanc, Jean‐Frédéric; Balabaud, Charles; Caldéraro, Julien; Laurent, Alexis; Letexier, Mélanie; Bioulac‐Sage, Paulette; Calvo, Fabien; Zucman‐Rossi, Jessica

doi:10.1038/ng.3389

Cited by 392 publications

(360 citation statements)

References 51 publications

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“…In tumors found post-treatment, these RNAs were strongly overexpressed, implying that rAAV integration played a causal role [79]. The observation that the internal transgene promoter was not necessary for the increase in tumor incidence is corroborated with a more recent study that noticed the same effect when even only a portion of the viral ITR was integrated [80]. The fact that a region of some rAAV2 ITRs contains a bidirectional binding site for a strong liver-specific transcription factor (HNF1α) aids the speculation that unforeseen integration of AAV ITRs can influence the expression of neighboring genes, similar to the situation observed following retroviral integration [72,81].…”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 80%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 80%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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show abstract

“…However, it is very challenging for the delivery of the CRISPR‐Cas9 system into cells or tissues because the plasmid encoding both Cas9 and sgRNA has strong negative charges and large size (usually exceeds 10 000 bp). Although viral vectors show high‐efficiency of gene transfection, they can result in mutagenesis, carcinogenesis, or other undesired consequences 6. Nonviral delivery methods such as membrane deformation7 or hydrodynamic injection8, 9 have been used to deliver plasmid DNA expressing Cas9 and sgRNA, but the possible damage of the target cells and/or the unsatisfactory delivery efficiency compromise the gene editing efficacy.…”

Section: Introductionmentioning

confidence: 99%

Genome Editing for Cancer Therapy: Delivery of Cas9 Protein/sgRNA Plasmid via a Gold Nanocluster/Lipid Core–Shell Nanocarrier

et al. 2017

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The type II bacterial clustered, regularly interspaced, short palindromic repeats (CRISPR)‐Cas9 (CRISPR‐associated protein) system (CRISPR‐Cas9) is a powerful toolbox for gene‐editing, however, the nonviral delivery of CRISPR‐Cas9 to cells or tissues remains a key challenge. This paper reports a strategy to deliver Cas9 protein and single guide RNA (sgRNA) plasmid by a nanocarrier with a core of gold nanoclusters (GNs) and a shell of lipids. By modifying the GNs with HIV‐1‐transactivator of transcription peptide, the cargo (Cas9/sgRNA) can be delivered into cell nuclei. This strategy is utilized to treat melanoma by designing sgRNA targeting Polo‐like kinase‐1 (Plk1) of the tumor. The nanoparticle (polyethylene glycol‐lipid/GNs/Cas9 protein/sgPlk1 plasmid, LGCP) leads to >70% down‐regulation of Plk1 protein expression of A375 cells in vitro. Moreover, the LGCP suppresses melanoma progress by 75% on mice. Thus, this strategy can deliver protein‐nucleic acid hybrid agents for gene therapy.

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“…53 What is clear from a number of reports is that mice treated in the neonatal period with high doses of rAAV that contains strong promoter-enhancer elements, or vectors that target integration into Rian, have a very high chance of developing HCC, and in the HCC, remnants of the vector will be likely be present in Mir341. However, it needs to be emphasized that distinct, non-Mir341 rAAV integrations within Rian do occur and appear pathogenic.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models

2017

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Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas

Cited by 392 publications

References 51 publications

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Genome Editing for Cancer Therapy: Delivery of Cas9 Protein/sgRNA Plasmid via a Gold Nanocluster/Lipid Core–Shell Nanocarrier

Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models

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