Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis
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 m...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117301324 |
| _version_ | 1819066448019980288 |
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| author | Da Sun Bhubanananda Sahu Songqi Gao Rebecca M. Schur Amita M. Vaidya Akiko Maeda Krzysztof Palczewski Zheng-Rong Lu |
| author_facet | Da Sun Bhubanananda Sahu Songqi Gao Rebecca M. Schur Amita M. Vaidya Akiko Maeda Krzysztof Palczewski Zheng-Rong Lu |
| author_sort | Da Sun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T16:02:31Z |
| format | Article |
| id | doaj.art-83fc4a4df7e748068a175bb78bcf769e |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-21T16:02:31Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-83fc4a4df7e748068a175bb78bcf769e2022-12-21T18:57:57ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-06-017C425210.1016/j.omtn.2017.02.005Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital AmaurosisDa Sun0Bhubanananda Sahu1Songqi Gao2Rebecca M. Schur3Amita M. Vaidya4Akiko Maeda5Krzysztof Palczewski6Zheng-Rong Lu7Case Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44140, USACase Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USACase Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44140, USACase Center for Biomolecular Engineering and Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USADevelopment 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.http://www.sciencedirect.com/science/article/pii/S2162253117301324Non-viral gene deliverymultifunctional lipidgene replacement therapyLeber’s congenital amaurosisRPE65 protein |
| spellingShingle | Da Sun Bhubanananda Sahu Songqi Gao Rebecca M. Schur Amita M. Vaidya Akiko Maeda Krzysztof Palczewski Zheng-Rong Lu Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis Molecular Therapy: Nucleic Acids Non-viral gene delivery multifunctional lipid gene replacement therapy Leber’s congenital amaurosis RPE65 protein |
| title | Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis |
| title_full | Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis |
| title_fullStr | Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis |
| title_full_unstemmed | Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis |
| title_short | Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis |
| title_sort | targeted multifunctional lipid eco plasmid dna nanoparticles as efficient non viral gene therapy for leber s congenital amaurosis |
| topic | Non-viral gene delivery multifunctional lipid gene replacement therapy Leber’s congenital amaurosis RPE65 protein |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117301324 |
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