Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.
Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.
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DOI：
10.1038/gt.2016.87
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发表时间：
2017-03
期刊：
影响因子：
5.1
通讯作者：
Baum BJ
中科院分区：
文献类型：
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作者：
Alevizos I;Zheng C;Cotrim AP;Liu S;McCullagh L;Billings ME;Goldsmith CM;Tandon M;Helmerhorst EJ;Catalán MA;Danielides SJ;Perez P;Nikolov NP;Chiorini JA;Melvin JE;Oppenheim FG;Illei GG;Baum BJ
我们在一项放射诱导的唾液功能减退的临床试验中评估了5名受试者中AdhAQP 1给药的晚期效应（http：www.clinicaltrials.gov/ct/show/NCT00372320? order=）.所有这些均被鉴定为最初对人水通道蛋白-1（hAQP 1）基因转移有反应（Baum et al，2012）。在AdhAQP 1递送至一侧腮腺后，对他们进行了3-4年的随访。每隔一段时间，我们检查唾液流量，口干症状，唾液成分，载体的存在和疗效，在目标腺体，临床实验室数据，和不良事件。治疗后3-4.7年，所有患者的腮腺血流均显著增加（高于基线71-500%），症状改善约2-3年。[Na+]和[Cl−]的一些变化与唾液流量升高一致，但腮腺关键蛋白的分泌没有一致的变化。没有临床显著的不良事件，实验室参数也没有一致的负变化。1例受试者在治疗后3.1年接受了靶向腮腺的空芯针活检，显示腺泡细胞膜（而非导管细胞膜）中存在hAQP 1蛋白的证据。所有对hAQP 1基因转移有反应的受试者最初都有更长时间的益处。第一代腺病毒载体通常产生转运效应，但这些数据表明，有益的效果可以持续数年后，腮腺交付。
We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer (Baum et al, 2012). They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data, and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~ 2-3 years. There were some changes in [Na+] and [Cl−] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.