Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors.
Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors.
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同基因 AAV 伪颗粒增强 AAV 载体的基因转导
DOI：
10.1016/j.omtm.2016.12.004
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发表时间：
2017-03-17
期刊：
影响因子：
--
通讯作者：
Xiao W
中科院分区：
文献类型：
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作者：
Wang Q;Dong B;Pokiniewski KA;Firrman J;Wu Z;Chin MP;Chen X;Liu L;Xu R;Diao Y;Xiao W
腺相关病毒（AAV）载体已成为安全有效的基因治疗平台。一个复杂之处在于，在AAV载体生产过程中总是产生大量的空颗粒作为杂质。然而，这种颗粒对AAV载体性能的影响仍不清楚。在这里，我们系统地评估了三种类型的“空”AAV颗粒的生物学性质：具有源自相应的完整颗粒的DNA的部分AAV基因组的同基因假载体、具有与相应的完整颗粒不同的部分基因组的同种异体假载体和衣壳内没有DNA的空假载体。过量的同基因颗粒在体内和体外均增加相应的完整AAV载体转基因表达。然而，在无效或同种异体颗粒中未观察到此类效应。这些假AAV颗粒之间观察到的差异可归因于促进相应完整AAV颗粒的互补DNA合成的同源假载体DNA。我们的研究表明，假载体中的DNA含量在决定其对AAV转导的影响方面起着关键作用。当比较AAV载体性能时，应充分评估残留“空”颗粒的影响。同源AAV假载体可用于增强基因治疗的功效。
Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of “empty” AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo-vectors with no DNA inside the capsids. The syngeneic particles in excess increased the corresponding full AAV vector transgene expression both in vivo and in vitro. However, such effects were not observed with null or allogeneic particles. The observed differences among these pseudo-AAV particles may be ascribed to the syngeneic pseudo-vector DNA facilitating the complementary DNA synthesis of the corresponding full AAV particles. Our study suggests that the DNA content in the pseudo-vectors plays a key role in dictating their effects on AAV transduction. The effects of residual “empty” particles should be adequately assessed when comparing AAV vector performance. The syngeneic AAV pseudo-vectors may be used to enhance the efficacy of gene therapy.