Gene therapy for acute lung injury.
Gene therapy for acute lung injury.
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DOI：
10.1007/s001340051128
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发表时间：
2000
影响因子：
38.9
通讯作者：
Stecenko AA
中科院分区：
文献类型：
--
作者：
Brigham KL;Stecenko AA
生物科学向分子生物学时代的显著转变为人类疾病治疗的新疗法的开发带来了巨大的希望。事实上，这项技术的存在可以精细地分析遗传物质，并以几乎任何所需的形式构建DNA，这是有望迅速转化为临床医学并最终治愈基因决定的疾病的基础；囊性纤维化是此类肺部疾病的主要例子。这一承诺没有兑现，至少没有在预期的时间框架内兑现。这一结果既不是因为理论基础有问题，也不是因为分子生物学的工具不足。魔鬼过去和现在都存在于细节中。如何将DNA以足够的数量输送到所需的细胞靶点，以达到所需的效果？病毒载体受到了最多的关注，但事实证明，病毒载体既有理论问题，也有实际问题。在肺部，这些媒介并没有实现它们最初的承诺。非基于病毒的策略在一般意义上是有效的，但体内基因传递的效率一直是一个限制。此外，临床和临床前研究的实验终点通常是为了证明现象学而不是潜在的疗效而设计的。而且，为什么要将基因治疗的潜力限制在遗传性疾病上呢？事实上，通过增加或减少特定基因在肺部的表达来治疗获得性疾病可能比治疗遗传性疾病更容易，因为对转基因表达持续时间的要求不那么严格。在过去的二十年里，我们已经对急性肺损伤的发病机制有了足够的了解，可以预测增加(或减少)某些生物活性介质的产生应该是有益的。编码其中一些介体的基因已经被克隆，并构建了表达这些基因的结构。现在可以使用病毒或非病毒策略将表达载体输送到肺部，而且由于急性肺损伤的预后很差，而且还没有发现有效的药物，这似乎是一个很好的基因治疗的临床靶点。在临床前研究中，我们已经证明，编码环氧合酶基因组成形式的基因(COX-1)的表达增加会导致肺组织产生更多的前列环素和前列腺素E_2，并抑制内毒素诱导的肺动脉高压和肺水肿。更多的研究表明，在培养和体内的人类呼吸道上皮细胞中，α-1抗胰蛋白酶基因的表达增加具有抗病毒和抗炎的作用，这是转基因产物的细胞外浓度无法预测的。因此，急性肺损伤是基因治疗的合理靶点，到目前为止的证据表明，目前的技术足够强大，可以追求这一新领域来治疗这种毁灭性的疾病。
The remarkable transition of biological science into the age of molecular biology held great promise for development of new therapies for treatment of human disease. The fact that the technology exists for analyzing genetic material in exquisite detail and constructing DNA in virtually any desired form was the basis for promising rapid translation into clinical medicine and the final cure for genetically determined diseases; cystic fibrosis is the prime example of such a lung disease. The promise was not kept, at least not in a time frame which was expected. That result is neither because the rationale was faulty nor because the tools of molecular biology were wanting. The devil was and is in the details. How do you deliver DNA to the desired cell targets in amounts sufficient to accomplish the desired effect? Viral vectors have received the most attention, but viral vectors have proven to have both theoretical and practical problems. In the lungs, these vectors have not fulfilled their original promise. Non-viral based strategies work in a general sense, but efficiency of gene delivery in vivo has been a limitation. In addition, the experimental end points in both clinical and preclinical investigation have been most often designed to demonstrate phenomenology rather than potential efficacy. And, why limit the potential of gene therapy to inherited disease? In fact, treatment of acquired diseases by increasing or decreasing expression of a given gene in the lungs that would hasten recovery from an acquired disease might be easier than treating inherited disease because the requirements for duration of transgene expression would be less stringent. Over the past two decades, we have learned enough about the pathogenesis of acute lung injury to predict that increased (or decreased) production of certain biologically active mediators should be beneficial. Genes encoding some of these mediators have been cloned and constructs made which express the genes. It is now possible using either viral or non-viral strategies to deliver expression constructs to the lungs and, since acute lung injury has a dismal prognosis and no effective drugs have been identified, this seems a good clinical target for gene therapy. In preclinical studies, we have shown that increased expression of the gene encoding the constitutive form of the cyclooxygenase gene (COX-1) results in increased production of prostacyclin and PGE2 by the lungs and inhibits endotoxin induced pulmonary hypertension and edema. Additional studies demonstrate that increased expression of the alpha-1 antitrypsin gene in human respiratory epithelium in culture and in vivo has anti-viral and anti-inflammatory effects that are not predicted by extracellular concentrations of the transgene product. Thus, acute lung injury is a reasonable target for gene therapy, and evidence to date indicates that current technology is sufficiently robust to pursue this novel area for treatment of this devastating disease.
影响因子：
4.2
作者：
SIMON, RH;ENGELHARDT, JF;WILSON, JM
通讯作者：
WILSON, JM
DOI：
10.1165/ajrcmb.10.1.8292378
发表时间：
1994-01-01
影响因子：
6.4
作者：
CANONICO, AE;CONARY, JT;BRIGHAM, KL
通讯作者：
BRIGHAM, KL
影响因子：
3.1
作者：
BRIGHAM, KL;MEYRICK, B;BERRY, LC
通讯作者：
BERRY, LC