Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice

Dalwadi, Dhwanil A.; Torrens, Laura; Abril-Fornaguera, Jordi; Pinyol, Roser; Willoughby, Catherine E.; Posey, Jeffrey; Llovet, Josep M.; Lanciault, Christian; Russell, David W.; Grompe, Markus; Naugler, Willscott E.

doi:10.1016/j.ymthe.2020.10.018

Cited by 69 publications

(62 citation statements)

References 44 publications

(64 reference statements)

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“…HCC formation has been observed in murine studies with AAV vectors using other transgenes and was attributed to insertional mutagenesis (although the bulk of AAV vector genomes persists episomally, integration does occur). Interestingly, HCC only developed upon neonatal gene transfer but not in mice transduced as adults unless they were fed a HFD leading to NAFLD (55), which was associated with increased inflammation and hepatocyte proliferation, consistent with our findings. Other studies on AAV gene delivery to the liver have not detected NASH or HCC.…”

Section: Discussionsupporting

confidence: 89%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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Clotting Factor VIII (FVIII) is the protein deficient in hemophilia A (HA), an X chromosome-linked bleeding disorder affecting 24.6 per 100,000 males at birth. Scientists and clinical physicians have been striving hard to find a cure for this disease. Presently, HA therapy involves prophylactic infusion of plasma-derived or recombinant-derived FVIII. Recent clinical studies have reported success using recent adeno-associated-virus (AAV) vector mediated delivery of a FVIII gene. FVIII is a 330 kDa glycoprotein comprised of three domains (A1-A2-B-A3-C1-C2). The B domain is dispensable and B domain-deleted (BDD) FVIII is used in the clinic as an effective protein replacement therapy for HA. Previously, we observed that hydrodynamic tail vein injection of the BDD-FVIII vector resulted in FVIII aggregation and endoplasmic reticulum (ER) stress in murine livers. Additionally, mice that were exposed to transient ER stress and then fed a high fat diet (HFD) for 9 months developed hepatocellular carcinoma (HCC). Therefore, we deduced that ectopic transient expression of FVIII in hepatocytes of mice with subsequent HFD feeding may also develop HCC. Here, we tested hepatocyte expression of two BDD-FVIII variants in vivo. BDD-FVIII aggregates in the ER and induces hepatocyte apoptosis, and N6-FVIII is more efficiently folded and secreted from the ER and causes less hepatocyte apoptosis. We performed tail vein injections of vectors directing expression of BDD-FVIII or N6-BDD to hepatocytes of 6-week old mice. One week after injection, mice were fed 60% HFD for 65 weeks. We found that 50% of mice that received N6-BDD developed liver tumors; in contrast, 90% of mice given BDD-FVIII developed liver tumors. Of the mice injected with BDD-FVIII, 30% developed carcinomas and 60% developed adenomas. Similar masses were not observed in mice that received empty vector. These findings raise concerns about the safety of long-term ectopic expression of FVIII in hepatocytes during FVIII gene therapy

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Section: Discussionsupporting

confidence: 89%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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“…Currently, accumulating evidence has proved that targeted therapies may effectively treat HCC patients. 37 , 38 However, the rapid development of drug resistance weakened the clinical effects of targeted drugs. Thus, it is urgent to develop more novel HCC biomarkers and treatment strategies in HCC patients.…”

Section: Discussionmentioning

confidence: 99%

A miR-212-3p/SLC6A1 Regulatory Sub-Network for the Prognosis of Hepatocellular Carcinoma

Zhang

Wang²,

et al. 2021

CMAR

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Introduction Hepatocellular carcinoma (HCC) is a liver cancer with a poor prognosis. Owing to the complexity and limited pathogenic mechanism research on HCC, the molecular targeted therapy has been hindered. Methods In this study, we categorized transcriptome data into low-Myc and high-Myc expression groups in 365 HCC samples, screened the differentially expressed RNAs, including 441 DE-lncRNAs, 99 DE-miRNAs and 612 DE-mRNAs, constructed a lncRNA-miRNA-mRNA regulatory network, and selected a hub triple regulatory network through cytoHubba analysis. Through Gene ontology and KEGG pathway, a hub regulatory network was particularly enriched in the “Wnt signaling pathway” and “Cytochrome P450-arranged by substrate type” by Metascape. The prognostic genes in the hub regulatory network were evaluated by the RNA expression analysis, Kaplan–Meier (KM) survival analysis, and correlation analysis. Results The results showed that miR-212-3p/SLC6A1 axis was a potential prognostic model for HCC. Furthermore, IHC analysis showed down-regulated expression of SLC6A1 in HCC tissues and Alb-Cre;Myc mouse liver cancer tissues. The genetics and epigenetic analysis indicated that SLC6A1 expression was negatively correlated with DNA methylation. Immune infiltration analysis showed a negative relation between SLC6A1 and T cell exhaustion/monocyte in liver cancer tissues. Conclusion In summary, the study revealed that miR-212-3p/SLC6A1 axis could serve as a crucial therapeutic target for HCC.

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“…Overall, the risk of developing HCC following gene transfer with AAV vectors appears to be low. The extent to which underlying chronic hepatic inflammation (as was present in the clinical trial participant) may increase the risk of HCC following systemic AAV delivery [155] will require careful examination in human clinical trials, so that rare events are maximally informative. Vector design optimization (e.g., the use of tissue-specific promoters, minimizing total vg/kg exposure), long-term follow-up of trial participants (using liver imaging, with a low threshold for tissue examination) and capture of longterm outcomes in national and global gene therapy registries will be important steps to understand and improve the safety profile of AAV gene transfer.…”

Section: Aav Vector Integration Into the Host Genomementioning

confidence: 99%

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

Monahan

Négrier

Tarantino

et al. 2021

JCM

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Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.

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Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice

Cited by 69 publications

References 44 publications

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

A miR-212-3p/SLC6A1 Regulatory Sub-Network for the Prognosis of Hepatocellular Carcinoma

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

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