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

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

Monday, 29.07.2019

Silencing PSMA2 protein (Proteasome subunit alpha type-2) through AAV-mediated shRNA delivery slowed the progression of breast cancer tumors. This study, developed in collaboration by scientists from iBET and IPATIMUP represents an important milestone for the development of new onco-therapies based in AAV vectors.

 

Authors and Affiliations: 

Catarina Pinto1,2, Gabriela Silva1, Ana S. Ribeiro4, Mónica Oliveira4, Manuel Garrido1, Vanessa S. Bandeira1, André Nascimento1, Ana Sofia Coroadinha1,2, Cristina Peixoto1,2, Ana Barbas1,3, Joana Paredes4,5, Catarina Brito1,2, Paula M. Alves1,2

1-iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal

2-Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal

3-Bayer Portugal, Carnaxide, Portugal

4-i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal

5-IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, Porto, Portugal

 

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.

 

Journal:  Journal of Biotechnology

 

Linkhttps://www.sciencedirect.com/science/article/pii/S0168165619301804