AAV-mediated photoreceptor transduction of the pig cone-enriched retina.
AAV-mediated photoreceptor transduction of the pig cone-enriched retina.
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作者：
最近在临床试验中的成功支持使用腺相关病毒（AAV）载体用于由视网膜色素上皮（RPE）缺陷引起的视网膜疾病的基因治疗。相比之下，AAV介导的基因转移到视网膜光感受器（遗传性视网膜疾病的主要部位）的功效的证据不太可靠。此外，尽管AAV介导的RPE转导似乎是有效的，与所使用的血清型和所治疗的物种无关，但迄今为止尚未在大型动物模型中系统地研究AAV介导的光感受器基因转移，这也可以允许鉴定AAV介导的视网膜转导中的相关物种特异性差异。在本研究中，我们使用的猪视网膜，它具有高锥/杆比。该特征允许适当地评估视锥和视杆光感受器转导，并比较AAV 2/5和2/8的转导特征，这两种最有效的AAV载体血清型用于光感受器靶向。在这里，我们表明AAV 2/5和2/8转导RPE和光感受器两者。AAV2/8比AAV2/5更有效地感染和转导光感受器，类似于我们在鼠视网膜中观察到的。光感受器特异性视紫红质启动子的使用将转基因表达限制在猪视杆细胞和视锥细胞中，并导致与用测试的遍在启动子获得的光感受器转导水平相似的光感受器转导水平。最后，免疫学、毒理学和生物分布研究支持AAV视网膜下施用至大型猪视网膜的安全性。这里提供的关于AAV介导的锥体富集的猪视网膜的转导的数据可能会影响罕见和常见的严重光感受器疾病的基于基因的疗法的发展。
Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases.
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影响因子：
4.2
作者：
Cideciyan, Artur V.;Hauswirth, William W.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
影响因子：
4.2
作者：
Jacobson, Samuel G.;Boye, Sanford L.;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
成人灵长类动物红绿色色盲的基因疗法。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.2
作者：
Hauswirth, William W.;Aleman, Tomas S.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
DOI：
10.1073/pnas.182412299
发表时间：
2002-09-03
影响因子：
11.1
作者：
Gao, GP;Alvira, MR;Wilson, JM
通讯作者：
Wilson, JM