Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103, USA.
Hum Gene Ther. 2012 Apr;23(4):382-9. doi: 10.1089/hum.2011.200. Epub 2012 Mar 28.
Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector has been reported as a good candidate for intravascular gene delivery, but low levels of preexisting antibody titers against AAV in the blood abrogate cellular transduction within the CNS. In the present study we compared the effectiveness of vascular delivery and cerebrospinal fluid (CSF) delivery of AAV9 in transducing CNS tissue in nonhuman primates. Both delivery routes generated similar distribution patterns, although we observed a more robust level of transduction after CSF delivery. Consistent with previous reports administering AAV9, we found greater astrocytic than neuronal tropism via both routes, although we did find a greater magnitude of CNS transduction after CSF delivery compared with intravascular delivery. Last, we have demonstrated that delivery of AAV9 into the CSF does not shield against AAV antibodies. This has obvious implications when developing and/or implementing any clinical trial studies.
广泛分布的基因产物在临床相关水平在整个中枢神经系统一直具有挑战性。腺相关病毒 9 型（AAV9）载体已被报道为血管内基因传递的良好候选物，但血液中针对 AAV 的预先存在的抗体滴度低会阻止中枢神经系统内的细胞转导。在本研究中，我们比较了血管内和脑脊液（CSF）传递 AAV9 在非人类灵长类动物中枢神经系统组织中转导的效果。两种传递途径都产生了相似的分布模式，尽管我们观察到 CSF 传递后的转导水平更高。与之前报道的 AAV9 给药一致，我们发现通过两种途径观察到的星形胶质细胞比神经元的亲嗜性更大，尽管与血管内传递相比，我们确实发现 CSF 传递后的中枢神经系统转导程度更大。最后，我们已经证明，将 AAV9 递送到 CSF 中并不能防止 AAV 抗体。这在开发和/或实施任何临床试验研究时都具有明显的意义。
