Formulation and efficacy of ECO/pRHO-ABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model
| Autor: | Andrew L Schilb, Wenyu Sun, Josef H Scheidt, Amirreza Naderi, Songqi Gao, Krzysztof Palczewski, Da Sun, Sang-Joon Lee, Zheng-Rong Lu, Timothy S. Kern, Cheng Wei |
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| Rok vydání: | 2021 |
| Předmět: |
viruses
Genetic enhancement Biomedical Engineering Pharmaceutical Science SV40 enhancer Bioengineering Simian virus 40 02 engineering and technology Article Mice 03 medical and health sciences chemistry.chemical_compound Rare Diseases Plasmid Gene expression Genetics medicine Stargardt Disease Animals Nanotechnology Pharmacology & Pharmacy Enhancer Gene 030304 developmental biology 0303 health sciences Chemistry Neurosciences Genetic Therapy Gene Therapy Pharmacology and Pharmaceutical Sciences Transfection Plasmid DNA Chemical Engineering ECO Non-viral gene delivery 021001 nanoscience & nanotechnology medicine.disease Molecular biology Stargardt disease Mutation Nanoparticles ATP-Binding Cassette Transporters Sorbitol 0210 nano-technology Biotechnology |
| Zdroj: | J Control Release |
| ISSN: | 0168-3659 |
| Popis: | It is still a challenge to develop gene replacement therapy for retinal disorders caused by mutations in large genes, such as Stargardt disease (STGD). STGD is caused by mutations in ABCA4 gene. Previously, we have developed an effective non-viral gene therapy using self-assembled nanoparticles of a multifunctional pH-sensitive amino lipid ECO and a therapeutic ABCA4 plasmid containing rhodopsin promoter (pRHO–ABCA4). In this study, we modified the ABCA4 plasmid with simian virus 40 enhancer (SV40, pRHO–ABCA4–SV40) for enhanced gene expression. We also prepared and assessed the formulations of ECO/pDNA nanoparticles using sucrose or sorbitol as a stablilizer to develop consistent and stable formulations. Results demonstrated that ECO formed stable nanoparticles with pRHO–ABCA4–SV40 in the presence of sucrose, but not with sorbitol. The transfection efficiency in vitro increased significantly after introduction of SV40 enhancer for plasmid pCMV-ABCA4–SV40 with a CMV promoter. Sucrose didn’t affect the transfection efficiency, while sorbitol resulted in a fluctuation of the in vitro transfection efficiency. Subretinal gene therapy in Abca4(−/−) mice using ECO/pRHO–ABCA4 and ECO/pRHO–ABCA4–SV40 nanoparticles induced 36% and 29% reduction in A2E accumulation respectively. Therefore, the ECO/pABCA4 based nanoparticles are promising for non-viral gene therapy for Stargardt disease and can be expended for applications in a variety of visual dystrophies with mutated large genes. |
| Databáze: | OpenAIRE |
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