Evaluation of AAV-mediated delivery of shRNA to target basal-like breast cancer genetic vulnerabilities

Catarina Pinto, Gabriela Silva, Ana S. Ribeiro, Mónica Oliveira, Manuel Garrido, Vanessa S. Bandeira, André Nascimento, Ana Sofia Coroadinha, Cristina Peixoto, Ana Barbas, Joana Paredes, Catarina Brito, Paula M. Alves

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Adeno-associated viral vectors (AAV) for gene therapy applications are gaining momentum, with more therapies moving into later stages of clinical development and towards market approval, namely for cancer therapy. The development of cytotoxic vectors is often hampered by side effects arising when non-target cells are infected, and their production can be hindered by toxic effects of the transgene on the producing cell lines. In this study, we evaluated the potential of rAAV-mediated delivery of short hairpin RNAs (shRNA) to target basal-like breast cancer genetic vulnerabilities. Our results show that by optimizing the stoichiometry of the plasmids upon transfection and time of harvest, it is possible to increase the viral titers and quality. All rAAV-shRNA vectors obtained efficiently transduced the BLBC cell lines MDA-MB-468 and HCC1954. In MDA-MB-468, transduction with rAAV-shRNA vector targeting PSMA2 was associated with significant decrease in cell viability and apoptosis induction. Importantly, rAAV2-PSMA2 also slowed tumor growth in a BLBC mouse xenograft model, thus potentially representing a therapeutic strategy against this type of cancer.

Original languageEnglish
Pages (from-to)70-77
Number of pages8
JournalJournal of Biotechnology
Volume300
DOIs
Publication statusPublished - 20 Jul 2019

Keywords

  • AAV production
  • Adeno-associated viral vectors
  • Basal-like breast cancer
  • Gene therapy

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