Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna.
Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna.
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DOI：
10.1038/mtm.2014.51
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发表时间：
2014
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--
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腺相关病毒血清9型(AAV9)载体最近被证明当注射到脑脊液(CSF)中时可以转导整个非人类灵长类动物的中枢神经系统的细胞，这一发现可能导致一种微创方法来治疗影响整个中枢神经系统的遗传性和获得性疾病。我们研究了两种途径进入食蟹猴脑脊液的转导效率--腰椎穿刺法和枕下穿刺法。腰椎穿刺法是临床上常用的方法，枕下穿刺法是兽医中更常用的方法。我们发现，通过枕下穿刺法将载体输送到枕大池，实现基因转移到大脑的效率高达100倍。此外，我们还评估了AAV9介导的GFP在非人灵长类中枢神经系统中的炎症反应。我们发现，虽然基因转移后脑脊液淋巴细胞计数增加，但没有临床或组织学迹象表明免疫毒性。综上所述，这些数据表明，将AAV9基因转移到枕大池是实现中枢神经系统基因转移的有效方法，并表明采用这种不常见的注射方法进行人体试验可以极大地提高基因转移的效率。
Adeno-associated virus serotype 9 (AAV9) vectors have recently been shown to transduce cells throughout the central nervous system of nonhuman primates when injected into the cerebrospinal fluid (CSF), a finding which could lead to a minimally invasive approach to treat genetic and acquired diseases affecting the entire CNS. We characterized the transduction efficiency of two routes of vector administration into the CSF of cynomolgus macaques—lumbar puncture, which is typically used in clinical practice, and suboccipital puncture, which is more commonly used in veterinary medicine. We found that delivery of vector into the cisterna magna via suboccipital puncture is up to 100-fold more efficient for achieving gene transfer to the brain. In addition, we evaluated the inflammatory response to AAV9-mediated GFP expression in the nonhuman primate CNS. We found that while CSF lymphocyte counts increased following gene transfer, there were no clinical or histological signs of immune toxicity. Together these data indicate that delivery of AAV9 into the cisterna magna is an effective method for achieving gene transfer in the CNS, and suggest that adapting this uncommon injection method for human trials could vastly increase the efficiency of gene delivery.
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作者：
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通讯作者：
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DOI：
10.1038/mt.2011.157
发表时间：
2011-11
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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作者：
通讯作者：
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影响因子：
17.1
作者：
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