Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons
Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons
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DOI：
10.1038/mt.2009.71
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发表时间：
2009-07-01
影响因子：
12.4
通讯作者：
Barkats, Martine
中科院分区：
文献类型：
--
作者：
Duque, Sandra;Joussemet, Beatrice;Barkats, Martine
将治疗性基因递送至整个脊髓是治疗运动神经元（MN）疾病的主要挑战。病毒基因载体的全身给药将为治疗分子从血液到脊髓的长期递送提供最佳手段，但这种方法受到血脑屏障（BBB）的存在的阻碍。在这里，我们描述了第一个成功的研究MN转导成年动物静脉内（i.v.）自互补（sc）AAV9载体的递送（在小鼠中高达28%）。在成人中实现静脉内MN转导，而没有BBB的药理学破坏，并且转基因表达持续至少5个月。重要的是，这一发现成功地转化到大型动物中，证明了scAAV9基因有效地系统性递送到新生猫和成年猫脊髓。这种新的和非侵入性的程序提出了希望全脊髓纠正MN疾病，并可能导致新的基因治疗方案的发展，在病人。
Therapeutic gene delivery to the whole spinal cord is a major challenge for the treatment of motor neuron (MN) diseases. Systemic administration of viral gene vectors would provide an optimal means for the long-term delivery of therapeutic molecules from blood to the spinal cord but this approach is hindered by the presence of the blood-brain barrier (BBB). Here, we describe the first successful study of MN transduction in adult animals following intravenous (i.v.) delivery of self-complementary (sc) AAV9 vectors (up to 28% in mice). Intravenous MN transduction was achieved in adults without pharmacological disruption of the BBB and transgene expression lasted at least 5 months. Importantly, this finding was successfully translated to large animals, with the demonstration of an efficient systemic scAAV9 gene delivery to the neonate and adult cat spinal cord. This new and non-invasive procedure raises the hope of whole spinal cord correction of MN diseases and may lead to the development of new gene therapy protocols in patients.