2022
DOI: 10.3389/fmed.2022.1052318
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Optimized riboswitch-regulated AAV vector for VEGF-B gene therapy

Abstract: Gene therapy would greatly benefit from a method to regulate therapeutic gene expression temporally. Riboswitches are small RNA elements that have been studied for their potential use in turning transgene expression on or off by ligand binding. We compared several tetracycline and toyocamycin-inducible ON-riboswitches for a drug responsive transgene expression. The tetracycline-dependent K19 riboswitch showed the best control and we successfully applied it to different transgenes. The induction of gene express… Show more

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Cited by 7 publications
(4 citation statements)
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“…98 For example, an AAV-VEGF-B cassette with an ON riboswitch can be precisely activated for a desired time frame. 99 OFF and kill switches have been studied particularly in the context of CAR-T cells, where rapid shutoff strategies are desirable to regulate a relatively high risk of acute toxicity. 100 In PAD gene therapy, this kind of toxicity is likely to be less relevant than the challenge of adverse effects caused by prolonged transgene overexpression causing growth of aberrant vasculature.…”
Section: Aav Transduction Specificity and Transgene Regulationmentioning
confidence: 99%
“…98 For example, an AAV-VEGF-B cassette with an ON riboswitch can be precisely activated for a desired time frame. 99 OFF and kill switches have been studied particularly in the context of CAR-T cells, where rapid shutoff strategies are desirable to regulate a relatively high risk of acute toxicity. 100 In PAD gene therapy, this kind of toxicity is likely to be less relevant than the challenge of adverse effects caused by prolonged transgene overexpression causing growth of aberrant vasculature.…”
Section: Aav Transduction Specificity and Transgene Regulationmentioning
confidence: 99%
“…When comparing several different aptamer-controlled ribozymes for the control of therapeutic transgenes, K19 was identified as the best candidate [ 56 ]. An optimized construct containing two ribozymes connected by a 100 bp linker was shown to be successful in regulating AAV-mediated expression of the transgene VEGF-B in human 293T cells.…”
Section: Catalytically Active – Tetracycline Responsive Ribozymesmentioning
confidence: 99%
“…[35] Copyright 2022, Springer Nature. Aside from mutations, some studies have shown that modifying specific nucleotides, [46] optimizing the length and stability of the linker sequence, [34,47] and constructing logical gates with multiple riboswitches [48] can improve riboswitch regulatory properties. For instance, Yokobayashi's team optimized riboswitch performance by regulating the stability of key sequences.…”
Section: Improving Riboswitch Performancementioning
confidence: 99%
“…Current research has optimized tetracycline‐dependent K19 riboswitches and employed two to three riboswitches in series to expand dynamic range, and they have been effectively used for the induction and expression of several transgenes. [ 48 ] The optimization of riboswitch design is still necessary in the future to achieve efficient gene regulation in gene therapy.…”
Section: Multidimensional Applications Of Riboswitchesmentioning
confidence: 99%