Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis

Da Sun; Bhubanananda Sahu; Songqi Gao; Rebecca M. Schur; Amita M. Vaidya; Akiko Maeda; Krzysztof Palczewski; Zheng-Rong Lu

doi:10.1016/j.omtn.2017.02.005

Molecular Therapy: Nucleic Acids (Jun 2017)

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis

Da Sun,
Bhubanananda Sahu,
Songqi Gao,
Rebecca M. Schur,
Amita M. Vaidya,
Akiko Maeda,
Krzysztof Palczewski,
Zheng-Rong Lu

Affiliations

Da Sun: Case Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
Bhubanananda Sahu: Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Songqi Gao: Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44140, USA
Rebecca M. Schur: Case Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
Amita M. Vaidya: Case Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
Akiko Maeda: Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Krzysztof Palczewski: Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44140, USA
Zheng-Rong Lu: Case Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA

DOI: https://doi.org/10.1016/j.omtn.2017.02.005
Journal volume & issue: Vol. 7, no. C
pp. 42 – 52

Abstract

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Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber’s congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC). All-trans-retinylamine, which binds to interphotoreceptor retinoid-binding protein (IRBP), was incorporated into the nanoparticles via a polyethylene glycol (PEG) spacer for targeted delivery of pDNA into the retinal pigmented epithelium. The targeted ECO/pDNA nanoparticles provided high GFP expression in the RPE of 1-month-old Rpe65−/− mice after subretinal injection. Such mice also exhibited a significant increase in electroretinographic activity, and this therapeutic effect continued for at least 120 days. A safety study in wild-type BALB/c mice indicated no irreversible retinal damage following subretinal injection of these targeted nanoparticles. All-trans-retinylamine-modified ECO/pDNA nanoparticles provide a promising non-viral platform for safe and effective treatment of RPE-specific monogenic eye diseases such as LCA2.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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