General Considerations on the Biosafety of Virus-derived Vectors Used in Gene Therapy and Vaccination

Baldo, Aline; Akker, Eric van den; Bergmans, Hans; Lim, Filip; Pauwels, Kris

doi:10.2174/15665232113136660005

Cited by 61 publications

(50 citation statements)

References 30 publications

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“…In patients with hepatocellular carcinomas integration of AAV2 into known cancer genes was observed [145]. Moreover, AAV-based immunotherapy faces various issues regarding immunogenicity [146][147][148]. A substantial percentage of the population has already been in contact with the used virus and consequently shows pre-existing immunity limiting the efficacy of treatment [149,150].…”

Section: Dna-based Antibody Expression In Vivomentioning

confidence: 99%

mRNA as novel technology for passive immunotherapy

Schlake¹,

Theß²,

Thran³

et al. 2018

Cell. Mol. Life Sci.

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While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized with target-specific receptors. In either case, administration or expression of recombinant proteins plays a fundamental role. mRNA prepared by in vitro transcription (IVT) is increasingly appreciated as a drug substance for delivery of recombinant proteins. With its biological role as transient carrier of genetic information translated into protein in the cytoplasm, therapeutic application of mRNA combines several advantages. For example, compared to transfected DNA, mRNA harbors inherent safety features. It is not associated with the risk of inducing genomic changes and potential adverse effects are only temporary due to its transient nature. Compared to the administration of recombinant proteins produced in bioreactors, mRNA allows supplying proteins that are difficult to manufacture and offers extended pharmacokinetics for short-lived proteins. Based on great progress in understanding and manipulating mRNA properties, efficacy data in various models have now demonstrated that IVT mRNA constitutes a potent and flexible platform technology. Starting with an introduction into passive immunotherapy, this review summarizes the current status of IVT mRNA technology and its application to such immunological interventions.

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Section: Dna-based Antibody Expression In Vivomentioning

confidence: 99%

mRNA as novel technology for passive immunotherapy

Schlake¹,

Theß²,

Thran³

et al. 2018

Cell. Mol. Life Sci.

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“…1 The current paradigm centers on the use of integrating or non-integrating viral vectors to deliver a transgene of interest into a selected cell type; however, these methods must overcome potential concerns associated with insertional oncogenesis, and immune reactions that may impact safety and efficacy. 2,3 In contrast, genome-editing strategies use transient expression of an engineered, site-specific endonuclease capable of inducing a DNA double-strand break. Resolution of the targeted DNA doublestand break via the nonhomologous end joining pathway is error-prone and can be used to generate targeted mutations, leading to a lossof-function, or in some cases gain-of-function mutations in the disease-relevant targeted gene.…”

Section: Introductionmentioning

confidence: 99%

Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates

Peterson

Wang

Norman

et al. 2016

Blood

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• This study is the first to show that genome-editing approaches can modify multilineage, long-term repopulating cells in a large animal model. • We demonstrate that the persistence of genome-edited hematopoietic stem cells can be tracked in vivo in a mutation-specific manner.Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a promising novel technology for the treatment of many human diseases. Here, we evaluated whether the disruption of the C-C chemokine receptor 5 (CCR5) locus in pigtailed macaque HSPCs by zinc finger nucleases (ZFNs) was feasible. We show that macaque-specific CCR5 ZFNs efficiently induce CCR5 disruption at levels of up to 64% ex vivo, 40% in vivo early posttransplant, and 3% to 5% in long-term repopulating cells over 6 months following HSPC transplant. These genome-edited HSPCs support multilineage engraftment and generate progeny capable of trafficking to secondary tissues including the gut. Using deep sequencing technology, we show that these ZFNs are highly specific for the CCR5 locus in primary cells. Further, we have adapted our clonal tracking methodology to follow individual CCR5 mutant cells over time in vivo, reinforcing that CCR5 gene-edited HSPCs are capable of long-term engraftment. Together, these data demonstrate that genome-edited HSPCs engraft, and contribute to multilineage repopulation after autologous transplantation in a clinically relevant large animal model, an important step toward the development of stem cell-based genome-editing therapies for HIV and potentially other diseases as well. (Blood. 2016;127(20):2416-2426

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“…All measures (autoclave treatments for 30 min at 121°C under 1 atm pressure, 0.5% sodium hypochlorite, 5% phenol, or 2% glutaraldehyde) sufficient to eliminate the peril of adenoviral transmission have to be met to minimize risks (alcohol is not a good decontaminant for Ad), but we must not forget that RDAd do not replicate and should not, unless recombination and complementation occur, be able to shed from inoculated animals, and are thus even less likely to infect another organism. In the case of an RCAd, the risk is reduced to the range and tropism of the Ad; for example, human adenovirus is only known to replicate in two nonhuman species: cotton rat and hamster [93].…”

Section: Safeties and Risks Of Adenoviral Vectorsmentioning

confidence: 99%

Adenovirus as Tools in Animal Health

Rojas¹,

Sevilla²,

Martı́n³

2019

Adenoviruses

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Adenoviruses have long been identified as good candidates for use as viral vectors in gene therapy and as vaccines. These viruses can infect multiple cell types, while in division or in quiescence, and are relatively easy to manipulate so that parts of their genome can be replaced with exogenous genes. Progressive safety improvements in replication-deficient adenoviral vectors have been achieved with the second and third generation, and ending with the gutless adenoviral vectors. Adenoviral vectors are immunogenic and can act as adjuvants. Nonetheless, the potency of human recombinant adenoviral vaccines was below expectations in clinical trials mainly because of the pre-existing adenoviral immunity found in the general population. This drawback can however become advantageous in animal health, as no previous immunity to human adenoviral vectors exists in animals. Other viral vectors viruses are used as vaccine, but adenoviruses remain the most employed and promising recombinant vector in veterinary medicine. In this chapter, we review the generation of adenoviral vectors, the immune response they trigger, and their advantages and disadvantages for veterinary use in terms of safety and efficacy. This chapter also describes how recombinant adenoviral vectors can be integrated as tools for vaccination and immunomodulation in veterinary medicine.

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General Considerations on the Biosafety of Virus-derived Vectors Used in Gene Therapy and Vaccination

Cited by 61 publications

References 30 publications

mRNA as novel technology for passive immunotherapy

mRNA as novel technology for passive immunotherapy

Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates

Adenovirus as Tools in Animal Health

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