AAV-mediated liver-directed gene therapy.
AAV-mediated liver-directed gene therapy.
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DOI：
10.1007/978-1-61779-370-7_6
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Sands, Mark S.
中科院分区：
文献类型：
--
作者：
Sands, Mark S.
肝脏直接或间接参与许多重要过程，并受到许多遗传性疾病的影响。因此，许多遗传性疾病可以通过使用基因转移方法靶向肝脏来有效治疗。与肝定向基因治疗相关的挑战是肝细胞的有效靶向、载体基因组的稳定性和持续的高水平表达。这些障碍中的许多可以用腺相关病毒（AAV）基因转移载体克服。开发用于体内使用的第一个AAV基因转移载体基于AAV 2血清型。AAV 2具有广泛的向性，并且在体内相对有效地转导许多细胞类型，包括肝细胞。衣壳蛋白赋予血清学谱，并且已经表征了至少12种灵长类AAV血清型。重要的是，用不同衣壳蛋白假型化重组AAV载体可以显著改变向性。与AAV 2相比，AAV 8和AAV 9对肝细胞具有更高的亲和力。特别地，当与AAV 2相比时，AAV 8可以使每个转导细胞的肝细胞增加3 -4倍，并递送3-4倍的基因组。取决于剂量，AAV 8在门静脉内注射后可以在小鼠肝脏中覆盖高达90-95%的肝细胞。有趣的是，在静脉内注射后可以实现相当水平的转导。AAV载体的直接实质内注射也介导相对高水平的长期表达。可通过使用肝特异性启动子与AAV 8衣壳蛋白结合来赋予另外的特异性。除了治疗原代肝细胞缺陷外，还可以通过绕过肝脏的固定组织巨噬细胞、枯否细胞和限制肝细胞的表达来最小化对转基因产物的免疫反应。凭借AAV血清型和使用肝脏特异性启动子靶向肝细胞的能力，使研究人员能够测试新的治疗方法并回答基本的临床和生物学问题。
The liver is directly or indirectly involved in many essential processes and is affected by numerous inherited diseases. Therefore, many inherited diseases could be effectively treated by targeting the liver using gene transfer approaches. The challenges associated with liver-directed gene therapy are efficient targeting of hepatocytes, stability of the vector genome, and persistent high level expression. Many of these obstacles can be overcome with adeno-associated viral (AAV) gene transfer vectors. The first AAV gene transfer vector developed for in vivo use was based on the AAV2 serotype. AAV2 has a broad tropism and transduces many cell types, including hepatocytes, relatively efficiently in vivo. The capsid protein confers the serological profile and at least 12 primate AAV serotypes have already been characterized. Importantly, pseudotyping a recombinant AAV vector with different capsid proteins can dramatically alter the tropism. Both AAV8 and AAV9 have higher affinities for hepatocytes when compared to AAV2. In particular, AAV8 can transduce 3–4 fold more hepatocytes and deliver 3–4 fold more genomes per transduced cell when compared to AAV2. Depending on the dose, AAV8 can transduce up to 90–95% of hepatocytes in the mouse liver following intraportal vein injection. Interestingly, comparable levels of transduction can be achieved following intravenous injection. Direct intraparenchymal injection of an AAV vector also mediates relatively high level long term expression. Additional specificity can be conferred by using liver-specific promoters in conjunction with AAV8 capsid proteins. In addition to treating primary hepatocyte defects, immune reactions to transgene products can be minimized by circumventing the fixed tissue macrophages of the liver, Kupffer cells, and limiting expression to hepatocytes. The ability to target hepatocytes by virtue of the AAV serotype and the use of liver-specific promoters allows investigators to test novel therapeutic approaches and answer basic clinical and biological questions.
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DOI：
10.1073/pnas.96.5.2296
发表时间：
1999-03-02
影响因子：
11.1
作者：
Daly, TM;Vogler, C;Sands, MS
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影响因子：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0437941100
发表时间：
2003-03-04
影响因子：
11.1
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