Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy?

Chandler, Randy J.; LaFave, Matthew C.; Varshney, Gaurav K.; Burgess, Shawn M.; Venditti, Charles P.

doi:10.1038/mt.2016.17

Cited by 51 publications

(45 citation statements)

References 20 publications

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“…The safety profile of AAV vectors reflects the fact they are related to naturally occurring AAV, which are generally non‐pathogenic in humans. As has been discussed, recombinant AAV only rarely integrates into host DNA, minimising the potential for genotoxicity . Based on relatively limited data from 35 participants, one of the main adverse events that was observed in 17 of 35 participants (48.6%) across all trials was transient alanine aminotransferase (ALT) elevations (Table ), which has also been observed in previous GT trials utilising intramuscular injection .…”

Section: What Is Gene Therapymentioning

confidence: 90%

How to discuss gene therapy for haemophilia? A patient and physician perspective

et al. 2019

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Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno‐associated viral (AAV) vector‐mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising AAV antibodies. Gene therapy offers a life‐changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment.

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Section: What Is Gene Therapymentioning

confidence: 90%

How to discuss gene therapy for haemophilia? A patient and physician perspective

et al. 2019

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“…Alternatively, the use of artificial liposome-based vesicles 44 or exosome mimetics could address the issue of exosome contaminants. Similarly, to translate the current results to humans, careful assessment of exo-AAV vector biodistribution and genome integration profile 45,46 will have to be performed, owing to the fact that these vectors enter the cell via receptor-independent pathways and traffic to the nucleus with high efficiency.…”

Section: Discussionmentioning

confidence: 99%

Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

et al. 2017

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“…39 There have been reports of hepatocellular carcinoma in livers of mice treated with AAV vectors. [40][41][42][43] However, the examination of liver tissues from over 50 treated mice showed no evidence of neoplastic changes.…”

Section: Pathological Examination Of Liver Sections From Treated Twi mentioning

confidence: 98%

Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease

2020

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Introduction: Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. This results in defective myelination in the peripheral and central nervous systems due to low GALC activity. Treatment at this time is limited to hematopoietic stem cell transplantation (HSCT) in pre-symptomatic individuals. While this treatment extends the lives of treated individuals, most have difficulty walking by the end of the first decade due to peripheral neuropathy. Studies in the murine model of KD, twitcher (twi) combining bone marrow transplantation (BMT) with AAVrh10-mGALC showed a great extension of life from 40 days to about 400 days, with some living a full life time. Methods: In order to find the optimum conditions for dosing and timing of this combined treatment, twi mice were injected with five doses of AAVrh10-mGALC at different times after BMT. Survival, as well as GALC expression were monitored along with studies of sciatic nerve myelination and possible liver pathology. Results: Dosing had a pronounced effect on survival and measured GALC activity. There was window of time after BMT to inject the viral vector and see similar results, however delaying both the BMT and the viral injection shortened the lifespans of the treated mice. Lowering the viral dose too much decreased the correction of the sciatic nerve myelination. There was no evidence for hepatic neoplasia. Conclusion: These studies provide the conditions optimum for successfully treating the murine model of KD. There is some flexibility in dosing and timing to obtain a satisfactory outcome. These studies are critical to the planning of a human trial combining the "standard of care", HSCT, with a single iv injection of AAVrh10-GALC.

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Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy?

Cited by 51 publications

References 20 publications

How to discuss gene therapy for haemophilia? A patient and physician perspective

How to discuss gene therapy for haemophilia? A patient and physician perspective

Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease

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