Molecular therapy, 2019-03, Vol.27 (3), p.611-622
2019
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Details
- Autor(en) / Beteiligte
- Titel
- Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue
- Ist Teil von
- Molecular therapy, 2019-03, Vol.27 (3), p.611-622
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage. [Display omitted] Guenther et al. have developed a protease-activatable AAV provector to target diseased tissue microenvironments exhibiting elevated extracellular protease activity. The provector delivers transgenes to high-MMP-activity regions of the damaged heart following a myocardial infarction, with concomitant decreased delivery to many off-target organs, including the liver.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1525-0016eISSN: 1525-0024DOI: 10.1016/j.ymthe.2019.01.015Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6404099
- Format
- –
- Schlagworte
- AAV, activatable, adeno-associated virus, Animals, Antibodies, Neutralizing - metabolism, Blood Circulation - physiology, cardiac gene therapy, Cardiovascular disease, Cryoelectron Microscopy, Data collection, Dependovirus - genetics, Electron microscopy, Female, gene delivery, Gene therapy, Gene transfer, Gene Transfer Techniques, Genetic Therapy - methods, Genetic Vectors - genetics, Genomes, Grants, Heart failure, Heparan sulfate, Image processing, Immunogenicity, inflammation targeting, Insertion, Matrix metalloproteinase, Matrix Metalloproteinase 2 - metabolism, Matrix Metalloproteinase 7 - metabolism, Matrix Metalloproteinase 9 - metabolism, Mice, Inbred BALB C, Microenvironments, Microscopy, Myocardial infarction, Myocardium - metabolism, Myocardium - pathology, Original, Pathogenicity, Peptides, Proteinase, provector, stimulus responsive, Transgenes, Tropism, viral vector