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Research Article

Non-viral gene delivery utilizing RALA modulates sFlt-1 secretion, important for preeclampsia

    Ross McNally

    The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, BT9 7BL, Northern Ireland

    ,
    Abdelrahim Alqudah

    The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, BT9 7BL, Northern Ireland

    Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, 13133, Jordan

    ,
    Emma M McErlean

    School of Pharmacy, Queen's University Belfast, Northern Ireland, BT9 7BL, UK

    ,
    Claire Rennie

    School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia

    ,
    Nabila Morshed

    School of Mathematical & Physical Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia

    ,
    Amy Short

    School of Pharmacy, Queen's University Belfast, Northern Ireland, BT9 7BL, UK

    ,
    Kristine McGrath

    School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia

    ,
    Olga Shimoni

    School of Mathematical & Physical Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia

    ,
    Tracy Robson

    School of Pharmacy & Biomolecular Sciences, Irish Centre for Vascular Biology, RCSI University of Medicine & Health Sciences, Dublin, 02, YN77, Republic of Ireland

    ,
    Helen O McCarthy

    School of Pharmacy, Queen's University Belfast, Northern Ireland, BT9 7BL, UK

    &
    Lana McClements

    *Author for correspondence:

    E-mail Address: lana.mcclements@uts.edu.au

    The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, BT9 7BL, Northern Ireland

    School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, 2007, Australia

    Published Online:https://doi.org/10.2217/nnm-2021-0180

    Background: Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preeclampsia. Methods: A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in vivo in transgenic haploinsufficient (Fkbpl+/−) mice. RALA was also used in vitro to deliver human Flt1 (hFlt1) in trophoblast cells. Results: Serum stable and nontoxic RALA/DNA-based nanoparticles induced an increase in sFlt-1 protein levels in the blood and total protein in the urine; the effect was more pronounced in Fkbpl+/− mice. In vitro, RALA-hFlt nanoparticles significantly reduced secretion of sFlt-1 in trophoblast cells. Conclusion: The RALA-based genetic nanodelivery system can be safely and effectively applied to emulate preeclampsia-like features or reduce sFlt-1 levels in vitro.

    Lay abstract

    In this study, the investigators utilized a safe and effective approach to modulate an important circulating protein in pregnancy, sFlt-1, associated with the pregnancy complication, preeclampsia. Preeclampsia is a complex and multifactorial disease and a leading cause of death in pregnancy with no current effective treatment strategies. This is likely due to a lack of reliable preclinical models that replicate human disease. The authors demonstrate the feasibility of a new preeclampsia-like model based on the dysfunction of two key vascular proteins, sFlt-1 and FKBPL (an important protein involved in the development of new blood vessels), that could be utilized in the future for testing and development of new treatments targeting these important mechanisms in preeclampsia.

    Tweetable abstract

    Development of a new model of #preeclampsia using a serum-stable and safe nonviral gene delivery system, #RALA, to modulate #sFlt-1 secretion in #FKBPL knockdown mice in vivo or #trophoblasts in vitro.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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