Reply to “Wild-type AAV Insertions in Hepatocellular Carcinoma Do Not Inform Debate Over Genotoxicity Risk of Vectorized AAV”

Schmidt, Manfred; Gil-Fariña, Irene; Büning, Hildegard

doi:10.1038/mt.2016.48

Cited by 11 publications

(5 citation statements)

References 16 publications

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“…Whereas AAVs allow the targeting of tissues currently inaccessible with technologies such as LNPs, toxicity associated with AAVs has recently become recognized in non-human primates (NHPs) and in clinical trials at high doses 73 , 74 . Animal studies have also indicated that AAV genomic integration may lead to hepatocellular carcinoma 75 , although a causal link between liver tumours and AAVs has not been established in humans treated with recombinant AAV vectors 76 , 77 . Additionally, since AAV-based ABE delivery does not benefit from the transience of delivery methods such as engineered virus-like particles 2 or LNP-mediated mRNA delivery 44 , the off-target editing profile and immunogenicity of long-term expression of base editors will need to be evaluated for potential clinical applications.…”

Section: Discussionmentioning

confidence: 99%

Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors

et al. 2022

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The viral delivery of base editors has been complicated by their size and by the limited packaging capacity of adeno-associated viruses (AAVs). Typically, dual-AAV approaches based on trans-splicing inteins have been used. Here we show that, compared with dual-AAV systems, AAVs with size-optimized genomes incorporating compact adenine base editors (ABEs) enable efficient editing in mice at similar or lower doses. Single-AAV-encoded ABEs retro-orbitally injected in mice led to editing efficiencies in liver (66%), heart (33%) and muscle (22%) tissues that were up to 2.5-fold those of dual-AAV ABE8e, and to a 93% knockdown (on average) of human PCSK9 and of mouse Pcsk9 and Angptl3 in circulation, concomitant with substantial reductions of plasma cholesterol and triglycerides. Moreover, three size-minimized ABE8e variants, each compatible with single-AAV delivery, collectively offer compatibility with protospacer-adjacent motifs for editing approximately 82% of the adenines in the human genome. ABEs encoded within single AAVs will facilitate research and therapeutic applications of base editing by simplifying AAV production and characterization, and by reducing the dose required for the desired level of editing.

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Section: Discussionmentioning

confidence: 99%

Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors

et al. 2022

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“…63,64 A debate whether this extends to AAV vectors is ongoing. [65][66][67] Although there is substantially more evidence supporting no risk for insertional mutagenesis in animal models and AAV-treated patients with hemophilia, greater numbers of treated patients are still needed to completely rule out this as a potential risk. 18 Another potential toxicity, related specifically to AAV gene therapy for hemophilia A, has been described by recent research.…”

Section: Nonimmune Toxicities Related To Gene Transfermentioning

confidence: 99%

“…However, it is not clear that an ER stress response to FVIII occurred in AAV-treated patients with hemophilia A, as discussed by the investigators. 36 Nonetheless, preclinical studies have focused on engineering FVIII proteins that are more efficiently secreted from hepatocytes, 15,19,[67][68][69][70][71] including the FVIII variant FVIII-V3, which is now being evaluated in clinical trial (Table 1). In addition to ER stress, it was speculated that the mild liver toxicities observed in patients with hemophilia A may be related to viral particle trafficking, uncoating, and vector DNA induction of the DNA damage response.…”

Section: Nonimmune Toxicities Related To Gene Transfermentioning

confidence: 99%

Update on clinical gene therapy for hemophilia

Perrin

Herzog

Markusic

2019

Blood

154

143

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In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a lasting cure with a single drug administration. Near-to-complete correction of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) have now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral vectors with different viral capsids that have been engineered to express high-level, and in some cases hyperactive, coagulation factors were employed. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors (or alternative drugs that promote coagulation), and may therefore ultimately also reduce treatment costs. However, mild liver toxicities have been observed in some patients receiving high vector doses. In some but not all instances, the toxicities correlated with a T-cell response directed against the viral capsid, prompting use of immune suppression. In addition, not all patients can be treated because of preexisting immunity to viral capsids. Nonetheless, studies in animal models of hemophilia suggest that the approach can also be used for immune tolerance induction to prevent or eliminate inhibitory antibodies against coagulation factors. These can form in traditional protein replacement therapy and represent a major complication of treatment. The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development.

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“…Therefore, the hepatocellular carcinoma was likely caused by the metabolic complications of OTC deficiency rather than the adenoviral vector [13]. The ongoing clinical trial uses an adeno-associated virus vector that can insert its DNA into human genome, but it is still not established whether adeno-associated virus genome insertion is tumorigenic [14, 15]. HCA in OTC-deficient patients has not been previously reported.…”

Section: Discussionmentioning

confidence: 99%