Synthetic riboswitches for external regulation of genes transferred by replication-deficient and oncolytic adenoviruses

Ketzer, Patrick; Haas, Simon F.; Engelhardt, Sarah; Hartig, Jörg S.; Nettelbeck, Dirk M.

Synthetic riboswitches for external regulation of genes transferred by replication-deficient and oncolytic adenoviruses

Dateien

ketzer_211505.pdfGröße: 4.48 MBDownloads: 630

Datum

2012

Autor:innen

Ketzer, Patrick

Haas, Simon F.

Engelhardt, Sarah

Hartig, Jörg S.

Nettelbeck, Dirk M.

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Chemie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Nucleic Acids Research. 2012, 40(21), pp. e167-e167. ISSN 0305-1048. eISSN 1362-4962. Available under: doi: 10.1093/nar/gks734

Zusammenfassung

Therapeutic gene transfer by replication-defective viral vectors or, for cancer treatment, by replication-competent oncolytic viruses shows high promise for treatment of major diseases. To ensure safety, timing or dosing in patients, external control of therapeutic gene expression is desirable or even required. In this study, we explored the potential of artificial aptazymes, ligand-dependent self-cleaving ribozymes, as an innovative tool for regulation of therapeutic gene expression. Importantly, aptazymes act on RNA intrinsically, independent of regulatory protein–nucleic acid interactions and stoichiometry, are non-immunogenic and of small size. These are key advantages compared with the widely used inducible promoters, which were also reported to lose regulation at high copy numbers, e.g. after replication of oncolytic viruses. We characterized aptazymes in therapeutic gene transfer utilizing adenovectors (AdVs), adeno-associated vectors (AAVs) and oncolytic adenoviruses (OAds), which are all in advanced clinical testing. Our results show similar aptazyme-mediated regulation of gene expression by plasmids, AdVs, AAVs and OAds. Insertion into the 5′-, 3′- or both untranslated regions of several transgenes resulted in ligand-responsive gene expression. Notably, aptazyme regulation was retained during OAd replication and spread. In conclusion, our study demonstrates the fidelity of aptazymes in viral vectors and oncolytic viruses and highlights the potency of riboswitches for medical applications.

Fachgebiet (DDC)

540 Chemie

Zitieren

ISO 690

KETZER, Patrick, Simon F. HAAS, Sarah ENGELHARDT, Jörg S. HARTIG, Dirk M. NETTELBECK, 2012. Synthetic riboswitches for external regulation of genes transferred by replication-deficient and oncolytic adenoviruses. In: Nucleic Acids Research. 2012, 40(21), pp. e167-e167. ISSN 0305-1048. eISSN 1362-4962. Available under: doi: 10.1093/nar/gks734

BibTex

@article{Ketzer2012-11Synth-21150,
  year={2012},
  doi={10.1093/nar/gks734},
  title={Synthetic riboswitches for external regulation of genes transferred by replication-deficient and oncolytic adenoviruses},
  number={21},
  volume={40},
  issn={0305-1048},
  journal={Nucleic Acids Research},
  pages={e167--e167},
  author={Ketzer, Patrick and Haas, Simon F. and Engelhardt, Sarah and Hartig, Jörg S. and Nettelbeck, Dirk M.}
}

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