Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.
Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.
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用于针对小儿疾病的脊髓，大脑和周围组织的大物种中的全身基因递送。
DOI：
10.1038/mt.2011.157
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发表时间：
2011-11
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腺相关病毒9型（AAV9）是一种在静脉注射后将基因传递到整个中枢神经系统（CNS）的有力工具。脊髓性肌萎缩症（SMA）和溶酶体贮积症的儿科模型的临床前结果为将AAV9推进临床提供了令人信服的依据。一个重要的转化步骤是证明在不同年龄的大型动物中能有效靶向中枢神经系统。在本研究中，我们在食蟹猴身上测试了全身注射的AAV9，从出生到3岁给药以靶向中枢神经系统和外周组织。我们表明，在所有研究的时间点，AAV9都能有效穿过血脑屏障（BBB）。转基因表达主要在整个大脑的神经胶质细胞、背根神经节神经元以及脊髓内的运动神经元中被检测到，这为向SMA患者的转化提供了信心。全身注射也能有效地靶向骨骼肌和外周器官。为了特异性地靶向中枢神经系统，我们探索了将AAV9递送至脑脊液（CSF）。脑脊液注射能有效地靶向运动神经元，并将基因表达限制在中枢神经系统内，为年龄较大、体型较大的患者提供了一种替代的递送途径，并且可能降低生产要求。我们的研究结果支持将AAV9用于儿科人群疾病的中枢神经系统基因转移。
Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood–brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.