Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy
Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy
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DOI：
10.1089/hum.2018.079
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发表时间：
2018-12-18
影响因子：
4.2
通讯作者：
Eichler, Florian
中科院分区：
文献类型：
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作者：
Gong, Yi;Berenson, Anna;Eichler, Florian
编码过氧化物酶体ATP结合盒转运蛋白（ABCD 1）的基因突变会导致极长链脂肪酸（VLCFA）和神经退行性疾病肾上腺脑白质营养不良（ALD）的升高。在大多数成年人中，这表现为脊髓轴突病肾上腺脊髓神经病（AMN）。AMN中基于病毒的基因治疗的一个挑战是如何实现对整个脊髓的功能性基因校正，同时最大限度地减少可能导致毒性的体循环泄漏。在本研究中，我们使用渗透泵将腺相关病毒（AAV）载体递送到小鼠的腰椎脑脊液空间中。我们报告说，缓慢鞘内递送重组AAV血清型9（rAAV 9）实现了有效的基因转移跨越脊髓和背根神经节，证明了两种不同的转基因，GFP和ABCD 1。在Abcd 1（-/-）小鼠中，与对照组相比，连续rAAV 9-CBA-hABCD 1递送后的基因校正导致脊髓中VLCFA水平降低20%。转导的主要细胞类型是星形胶质细胞、血管内皮细胞和神经元。重要的是，与推注相比，通过渗透泵鞘内递送的rAAV 9减少了进入外周器官，特别是肝脏和心脏组织的全身渗漏。
Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter (ABCD1) cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated viral (AAV) vector into the lumbar cerebrospinal fluid space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated with two different transgenes, GFP and ABCD1. In the Abcd1(-/-) mouse, gene correction after continuous rAAV9-CBA-hABCD1 delivery led to a 20% decrease in VLCFA levels in spinal cord compared with controls. The major cell types transduced were astrocytes, vascular endothelial cells, and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, reduced systemic leakage into peripheral organs, particularly liver and heart tissue.