Engineering Adenoviral Vectors with Improved GBM Selectivity.
Engineering Adenoviral Vectors with Improved GBM Selectivity.
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DOI：
10.3390/v15051086
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发表时间：
2023-04-28
期刊：
影响因子：
--
通讯作者：
Parker AL
中科院分区：
文献类型：
--
作者：
Bates EA;Lovatt C;Plein AR;Davies JA;Siebzehnrubl FA;Parker AL
胶质母细胞瘤（GBM）是最常见和最具侵袭性的成人脑癌，接受标准治疗的患者的平均生存率约为15个月。表达治疗性转基因的溶瘤腺病毒代表了GBM的有希望的替代治疗。在迄今为止描述的许多人腺病毒血清型中，腺病毒5（HAdV-C5）在临床和实验上使用最多。然而，使用Ad 5作为抗癌剂可能受到HAdV-C5的天然高血清阳性率以及通过天然受体感染健康细胞的阻碍。为了探索替代的天然腺病毒嗜性是否更适合GBM治疗，我们使用来自替代血清型的纤维结蛋白对基于HAdV-C5的平台进行假型化。我们证明，腺病毒进入受体科萨基，腺病毒受体（CAR）和CD 46的GBM和健康的脑组织高度表达，而桥粒芯糖蛋白2（DSG 2）在GBM中表达水平较低。我们证明了腺病毒假型，接合CAR，CD 46和DSG 2，有效地抑制GBM细胞。然而，这些受体在非转化细胞上的存在呈现了脱靶效应和在健康细胞中的治疗性转基因表达的可能性。为了增强转基因表达对GBM的特异性，我们评估了肿瘤特异性启动子hTERT和生存素在GBM细胞系中选择性驱动报告基因表达的潜力。我们使用这些构建体证明了紧密的GBM特异性转基因表达，表明假型化和肿瘤特异性启动子方法的组合可以使更适合GBM的有效疗法的开发成为可能。
Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (HAdV-C5) has been the most utilised clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to HAdV-C5 coupled with the infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an HAdV-C5-based platform using the fibre knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptor coxsackie, adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at a low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance the specificity of transgene expression to GBM, we assessed the potential for tumour-specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tight GBM-specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour-specific promoter approaches may enable the development of efficacious therapies better suited to GBM.
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影响因子：
82.9
作者：
Gaggar, A;Shayakhmetov, DM;Lieber, A
通讯作者：
Lieber, A
基于人类腺病毒10型的低渗透价值，αVβ6整联蛋白选择性疗法的发展。
DOI：
10.1016/j.omto.2022.03.007
发表时间：
2022-06-16
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
Bates EA;Davies JA;Váňová J;Nestić D;Meniel VS;Koushyar S;Cunliffe TG;Mundy RM;Moses E;Uusi-Kerttula HK;Baker AT;Cole DK;Majhen D;Rizkallah PJ;Phesse T;Chester JD;Parker AL
通讯作者：
Parker AL
影响因子：
15.9
作者：
Ostrom, Quinn T.;Gittleman, Haley;Barnholtz-Sloan, Jill S.
通讯作者：
Barnholtz-Sloan, Jill S.
影响因子：
45.3
作者：
Lang, Frederick F.;Conrad, Charles;Fueyo, Juan
通讯作者：
Fueyo, Juan
DOI：
10.3390/v13050864
发表时间：
2021-05-08
期刊：
Viruses
影响因子：
--
作者：
Davies JA;Marlow G;Uusi-Kerttula HK;Seaton G;Piggott L;Badder LM;Clarkson RWE;Chester JD;Parker AL
通讯作者：
Parker AL