T Cell-Mediated Immune Responses to AAV and AAV Vectors

Ertl, Hildegund C. J.

doi:10.3389/fimmu.2021.666666

Cited by 54 publications

(38 citation statements)

References 122 publications

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“…Anti-AAV neutralizing antibodies and AAV capsid specific T cells exist in many people because of prior exposure to the common wide-type virus 10, 22 . AAV capsid antibodies may preclude transduction of AAV vectors and T-cell response may eliminate transduced human hepatocytes 10 .…”

Section: Discussionmentioning

confidence: 99%

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Zou

2022

Preprint

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Rational first-in-patient (FIP) dose selection is critical for successful clinical development of gene therapy. In this study, the author compared the performance of two allometric scaling approaches and body weight-based dose conversion approach for FIP dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy. The performance of the three approaches was examined using preclinical and clinical efficacy data of nine AAV vectors. In general, body weight-based direct conversion of effective doses in monkeys or dogs was more likely to underestimate FIP dose but worked better for one bioengineered vector with a high transduction efficiency specifically in humans. In contrast, allometric scaling between gene efficiency factor (logGEF) and body weight (logW) was likely to overestimate FIP dose but worked better than the other two approaches when vector capsid-specific T-cell responses were detected in patients. The third approach, allometric scaling between logGEF and W-0.25 was appropriate for FIP dose prediction in the absence of T-cell responses to AAV vectors or a dramatic difference in vector transduction efficiency between animals and humans. A decision tree was tentatively proposed to facilitate approach selection for FIP dose prediction in AAV-mediated hemophilia gene therapy.

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Section: Discussionmentioning

confidence: 99%

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Zou

2022

Preprint

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“…Much remains to be learned about the key molecular interactions of capsid with host factors, and one would anticipate continuing feedback into vector design over the coming years. There are also areas in which the salient molecular interactions remain largely uncharacterized, such as cellular immune responses, and so progress in vector delivery, at the moment, involves empirical mitigation strategies [ 35 , 198 ].…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry

Large

Silveria

Zane

et al. 2021

Viruses

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Human gene therapy has advanced from twentieth-century conception to twenty-first-century reality. The recombinant Adeno-Associated Virus (rAAV) is a major gene therapy vector. Research continues to improve rAAV safety and efficacy using a variety of AAV capsid modification strategies. Significant factors influencing rAAV transduction efficiency include neutralizing antibodies, attachment factor interactions and receptor binding. Advances in understanding the molecular interactions during rAAV cell entry combined with improved capsid modulation strategies will help guide the design and engineering of safer and more efficient rAAV gene therapy vectors.

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“…The transduction efficiency of dual rAAV vectors after systemic administration is understudied, but it is reasonable to assume that significantly higher AAV vector amounts are necessary to co-transduce a considerable percentage of target cells. However, higher rAAV dosage is associated with higher side effect risks, e.g., immune responses [ 59 ]. Therefore, further studies are necessary to investigate the principal suitability and the side effect profile of dual rAAV vectors after systemic administration.…”

Section: Main Textmentioning

confidence: 99%

Maybe you can turn me on: CRISPRa-based strategies for therapeutic applications

Becirovic

2022

Cell. Mol. Life Sci.

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Since the revolutionary discovery of the CRISPR-Cas technology for programmable genome editing, its range of applications has been extended by multiple biotechnological tools that go far beyond its original function as “genetic scissors”. One of these further developments of the CRISPR-Cas system allows genes to be activated in a targeted and efficient manner. These gene-activating CRISPR-Cas modules (CRISPRa) are based on a programmable recruitment of transcription factors to specific loci and offer several key advantages that make them particularly attractive for therapeutic applications. These advantages include inter alia low off-target effects, independence of the target gene size as well as the potential to develop gene- and mutation-independent therapeutic strategies. Herein, I will give an overview on the currently available CRISPRa modules and discuss recent developments, future potentials and limitations of this approach with a focus on therapeutic applications and in vivo delivery.

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T Cell-Mediated Immune Responses to AAV and AAV Vectors

Cited by 54 publications

References 122 publications

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry

Maybe you can turn me on: CRISPRa-based strategies for therapeutic applications

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