Da Sun, Wenyu Sun, Song-Qi Gao, Jonathan Lehrer, Hong Wang, Ryan Hall, Zheng-Rong Lu
{"title":"玻璃体内输送 PEG 化-ECO 质粒 DNA 纳米粒子用于斯塔加特病的基因治疗","authors":"Da Sun, Wenyu Sun, Song-Qi Gao, Jonathan Lehrer, Hong Wang, Ryan Hall, Zheng-Rong Lu","doi":"10.1007/s11095-024-03679-1","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Objective</h3><p>Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (<i>pGRK1-ABCA4-S/MAR</i>) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Pigmented <i>Abca4</i><sup><i>−/−</i></sup> knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of <i>ABCA4</i> in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>PEG-ELNP resulted in significant <i>ABCA4</i> expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. The PEG-ELNP also demonstrated excellent safety as shown by scanning laser ophthalmoscopy, and the eye function evaluation from electroretinogram.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Intravitreal delivery of the PEG-ELNP of <i>pGRK1-ABCA4-S/MAR</i> is a promising approach for gene therapy of Stargardt Disease, which can also be a delivery platform for gene therapy of other inherited retinal diseases.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Intravitreal Delivery of PEGylated-ECO Plasmid DNA Nanoparticles for Gene Therapy of Stargardt Disease\",\"authors\":\"Da Sun, Wenyu Sun, Song-Qi Gao, Jonathan Lehrer, Hong Wang, Ryan Hall, Zheng-Rong Lu\",\"doi\":\"10.1007/s11095-024-03679-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Objective</h3><p>Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (<i>pGRK1-ABCA4-S/MAR</i>) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>Pigmented <i>Abca4</i><sup><i>−/−</i></sup> knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of <i>ABCA4</i> in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG).</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>PEG-ELNP resulted in significant <i>ABCA4</i> expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. 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Intravitreal Delivery of PEGylated-ECO Plasmid DNA Nanoparticles for Gene Therapy of Stargardt Disease
Objective
Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (pGRK1-ABCA4-S/MAR) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease.
Methods
Pigmented Abca4−/− knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of ABCA4 in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG).
Results
PEG-ELNP resulted in significant ABCA4 expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. The PEG-ELNP also demonstrated excellent safety as shown by scanning laser ophthalmoscopy, and the eye function evaluation from electroretinogram.
Conclusions
Intravitreal delivery of the PEG-ELNP of pGRK1-ABCA4-S/MAR is a promising approach for gene therapy of Stargardt Disease, which can also be a delivery platform for gene therapy of other inherited retinal diseases.
期刊介绍：
Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to:
-(pre)formulation engineering and processing-
computational biopharmaceutics-
drug delivery and targeting-
molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)-
pharmacokinetics, pharmacodynamics and pharmacogenetics.
Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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