Wang Jianghua, Voutetakis Antonis, Mineshiba Fumi, Illei Gabor G, Dang Howard, Yeh Chih-Ko, Baum Bruce J
Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, MD 20892-1190, USA.
Hum Gene Ther. 2006 Apr;17(4):455-63. doi: 10.1089/hum.2006.17.455.
Key to the development of a useful clinical therapy is the minimization of side effects. Routine safety testing, however, does not provide information about the physiological status of many potentially useful gene transfer target sites. In this study, we evaluated the longitudinal effects of intrasalivary duct delivery of recombinant serotype 5 adenoviral (rAd5; 10(9)-10(10) particles/gland in rats) and recombinant serotype 2 adeno-associated viral (rAAV2; 10(8)-10(9) particles/gland in mice) vectors on salivary composition. Both vectors led to modest, transient alterations in several salivary components that thereafter returned to normal. The changes suggested two initial specific consequences of rAd5 and rAAV2 vector administration: (1) a modest breach of the mucosal barrier in the targeted glands, indicated by elevations in salivary albumin, total protein, and Na+ levels, and (2) an innate host response, indicated by transient elevations in either salivary lactoferrin and IgA levels (rAd5) or mucin (rAAV2). These studies are consistent with the notion that administration of modest doses of rAd5 and rAAV2 vectors to salivary glands for a therapeutic purpose can be accomplished without severe or permanent injury to the target tissue, or compromise to its essential exocrine physiological function.
开发一种有效的临床治疗方法的关键在于将副作用降至最低。然而，常规安全性测试并不能提供许多潜在有用的基因转移靶位点的生理状态信息。在本研究中，我们评估了经唾液腺导管递送重组5型腺病毒（rAd5；大鼠中10⁹ - 10¹⁰颗粒/腺体）和重组2型腺相关病毒（rAAV2；小鼠中10⁸ - 10⁹颗粒/腺体）载体对唾液成分的长期影响。两种载体均导致几种唾液成分出现适度的短暂改变，之后又恢复正常。这些变化提示了rAd5和rAAV2载体给药后的两个初始特定后果：（1）靶向腺体的黏膜屏障出现适度破坏，表现为唾液白蛋白、总蛋白和Na⁺水平升高；（2）宿主的先天反应，表现为唾液乳铁蛋白和IgA水平（rAd5）或黏蛋白（rAAV2）短暂升高。这些研究与以下观点一致，即出于治疗目的向唾液腺给予适度剂量的rAd5和rAAV2载体，可以在不严重或永久性损伤靶组织，也不损害其基本外分泌生理功能的情况下实现。
