title: Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno-associated viral vectors.
abstract: Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.|Department of Hematology and Oncology, Augsburg Medical Center, Stenglinstr, Augsburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Trepel
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Körbelin
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Spies
authors.affiliation: University Hospital Heidelberg, Heidelberg, and DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Im Neuenheimer Feld 410, Heidelberg, Germany.
authors.forename: M B
authors.initials: MB
authors.lastname: Heckmann
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hunger
authors.affiliation: Department of Cell and Gene Therapy, Bone Marrow Transplantation Unit Research, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Fehse
authors.affiliation: University Hospital Heidelberg, Heidelberg, and DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Im Neuenheimer Feld 410, Heidelberg, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Kleinschmidt
authors.affiliation: University Hospital Heidelberg, Heidelberg, and DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Im Neuenheimer Feld 410, Heidelberg, Germany.
authors.forename: O J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistr, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Michelfelder
mesh_terms: D000818:Animals; D000229:Dependovirus; D005260:Female; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage
chemical_list: D035683:MicroRNAs