title: Preclinical in vivo evaluation of the safety of a multi-shRNA-based gene therapy against HIV-1.
abstract: Highly active antiretroviral therapy (HAART) has significantly improved the quality of life and the life expectancy of HIV-infected individuals. Still, drug-induced side effects and emergence of drug-resistant viral variants remain important issues that justify the exploration of alternative therapeutic options. One strategy consists of a gene therapy based on RNA interference to induce the sequence-specific degradation of the HIV-1 RNA genome. We have selected four potent short hairpin RNA (shRNA) candidates targeting the viral capside, integrase, protease and tat/rev open-reading frames and screened the safety of them during human hematopoietic cell development, both in vitro and in vivo. Although the four shRNA candidates appeared to be safe in vitro, one shRNA candidate impaired the in vivo development of the human immune system in Balb/c Rag2(-/-)IL-2Rγc(-/-) (BRG) mice. The three remaining shRNA candidates were combined into one single lentiviral vector (LV), and safety of the shRNA combination during human hematopoietic cell development was confirmed. Overall, we demonstrate here the preclinical in vivo safety of a LV expressing three shRNAs against HIV-1, which is proposed for a future Phase I clinical trial.Molecular Therapy-Nucleic Acids (2013) 2, e120; doi:10.1038/mtna.2013.48; published online 3 September 2013.
authors.affiliation: 1] Department of Medical Microbiology, Laboratory of Experimental Virology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands [2] Laboratory of Immunity and Infection, Institut National de la Santé et de la Recherche Médicale, INSERM UMR-S 945, and Université Pierre et Marie Curie, UPMC Univ Paris 06, 91 Bld de l'Hôpital, 75013 Paris, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Centlivre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Legrand
authors.forename: Sofieke
authors.initials: S
authors.lastname: Klamer
authors.forename: Ying Poi
authors.initials: YP
authors.lastname: Liu
authors.forename: Karin
authors.initials: K
authors.lastname: Jasmijn von Eije
authors.forename: Martino
authors.initials: M
authors.lastname: Bohne
authors.forename: Esther Siteur-van
authors.initials: ES
authors.lastname: Rijnstra
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.forename: Bianca
authors.initials: B
authors.lastname: Blom
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout