Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles.
Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles.
复制标题
使用PEG-ECO/PGRK1-ABCA4-S/MAR纳米颗粒的Stargardt疾病的有效基因治疗。
DOI：
10.1016/j.omtn.2022.08.026
复制
发表时间：
2022-09-13
期刊：
影响因子：
--
通讯作者：
Lu, Zheng-Rong
中科院分区：
文献类型：
--
作者：
Sun, Da;Sun, Wenyu;Gao, Song-Qi;Lehrer, Jonathan;Naderi, Amirreza;Wei, Cheng;Lee, Sangjoon;Schilb, Andrew L.;Scheidt, Josef;Hall, Ryan C.;Traboulsi, Elias I.;Palczewski, Krzysztof;Lu, Zheng-Rong
Stargardt病（STGD）是最常见的遗传性视网膜遗传性疾病，通常由ABCA 4突变引起。基因治疗有望有效治疗单基因视网膜疾病。然而，临床上批准的腺相关病毒（AAV）载体不具有大基因（例如ABCA 4）的负载能力。由（1-氨基乙基）亚氨基双[N-（油酰基半胱氨酰基-1-氨基乙基）丙酰胺（ECO;多功能pH敏感/可电离氨基脂质）和质粒DNA组成的自组装纳米颗粒产生与AAV 2衣壳相当或更好的基因转染。稳定的PEG-ECO/pGRK 1-ABCA 4-S/MAR纳米颗粒在Abca 4 −/−小鼠的光感受器中产生特异性和延长的ABCA 4表达，并显着抑制眼睛中有毒A2 E的积累。多次视网膜下注射可增强基因表达和治疗效果，3次给药后Abca 4 −/−小鼠中A2 E蓄积减少约69%。在多次注射纳米颗粒后观察到非常轻微的炎症。PEG-ECO/pGRK 1-ABCA 4-S/MAR纳米颗粒是一种有前途的非病毒介导的STGD 1型（STGD 1）基因治疗方式。Sun等人开发了一种新的基于脂质纳米颗粒的Stargardt病（STGD）基因疗法，该疗法在Abca 4 −/−小鼠（STGD模型）的光感受器中产生特异性和延长的ABCA 4基因表达，并通过单次和重复治疗显著抑制毒性A2 E的积累，具有良好的安全性。
Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in ABCA4. Gene therapy has the promise to effectively treat monogenic retinal disorders. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as ABCA4. Self-assembly nanoparticles composed of (1-aminoethyl)iminobis[N-(oleoylcysteinyl-1-amino-ethyl)propionamide (ECO; a multifunctional pH-sensitive/ionizable amino lipid) and plasmid DNA produce gene transfection comparable with or better than the AAV2 capsid. Stable PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles produce specific and prolonged expression of ABCA4 in the photoreceptors of Abca4−/− mice and significantly inhibit accumulation of toxic A2E in the eye. Multiple subretinal injections enhance gene expression and therapeutic efficacy with an approximately 69% reduction in A2E accumulation in Abca4−/− mice after 3 doses. Very mild inflammation was observed after multiple injections of the nanoparticles. PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles are a promising non-viral mediated gene therapy modality for STGD type 1 (STGD1). Sun et al. developed a novel lipid nanoparticle-based gene therapy for Stargardt disease (STGD) that produced specific and prolonged ABCA4 gene expression in the photoreceptors of Abca4−/− mice (STGD model) and significantly inhibited accumulation of toxic A2E through single and repeated treatments with an excellent safety profile.
登录
查看更多内容
影响因子：
4
作者：
Ayat, Nadia R.;Sun, Zhanhu;Lu, Zheng-Rong
通讯作者：
Lu, Zheng-Rong
影响因子：
56.9
作者：
Allikmets, R;Shroyer, NF;Leppert, M
通讯作者：
Leppert, M
影响因子：
4.4
作者：
Binley, Katie;Widdowson, Peter;Mitrophanous, Kyriacos A.
通讯作者：
Mitrophanous, Kyriacos A.
影响因子：
5.1
作者：
Kong, J.;Kim, S-R;Allikmets, R.
通讯作者：
Allikmets, R.
影响因子：
4.8
作者：
Maeda, Akiko;Maeda, Tadao;Palczewski, Krzysztof
通讯作者：
Palczewski, Krzysztof