Abstract：
Adeno-associated virus (AAV)-based vectors are commonly used for delivering transgenes in gene therapy studies, but they are also known to cause dorsal root ganglia (DRG) and peripheral nerve toxicities in animals. However, the functional implications of these pathologic findings and their time course remain unclear. At 2, 4, 6, and 8 weeks following a single dose of an AAV9 vector carrying human frataxin transgene in rats, non-standard functional assessments, including von Frey filament, electrophysiology, and Rotarod tests, were conducted longitudinally to measure allodynia, nerve conduction velocity, and coordination, respectively. Additionally, DRGs, peripheral nerves, brain and spinal cord were evaluated histologically and circulating neurofilament light chain (NfL) was quantified at 1, 2, 4, and 8 weeks, respectively. At 2 and 4 weeks after dosing, minimal-to-moderate nerve fiber degeneration and neuronal degeneration were observed in the DRGs in some of the AAV9 vector-dosed animals. At 8 weeks, nerve fiber degeneration was observed in DRGs, with or without neuronal degeneration, and in sciatic nerves of all AAV9 vector-dosed animals. NfL values were higher in AAV9 vector-treated animals at weeks 4 and 8 compared with controls. However, there were no significant differences in the three functional endpoints evaluated between the AAV9 vector- and vehicle-dosed animals, or in a longitudinal comparison between baseline (predose), 4, and 8 week values in the AAV9 vector-dose animals. These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.
摘要：
在基因治疗研究中，基于腺相关病毒（AAV）的载体通常用于传递转基因。但已知它们也会引起动物的背根神经节（DRG）和周围神经毒性。然而,这些病理结果的功能意义及其时程尚不清楚.在大鼠单剂量携带人共济失调蛋白转基因的AAV9载体后2、4、6和8周，非标准功能评估，包括vonFrey灯丝,电生理学,和旋转试验，纵向测量异常性疼痛，神经传导速度,协调,分别。此外,DRGs,周围神经,在第1、2、4和8周时对大脑和脊髓进行组织学评估，并对循环神经丝轻链（NfL）进行定量，分别。给药后2周和4周，在一些AAV9载体给药动物的DRGs中观察到轻度至中度神经纤维变性和神经元变性.在8周的时候,在DRGs中观察到神经纤维变性，有或没有神经元变性，和所有AAV9载体剂量动物的坐骨神经。与对照相比,在第4周和第8周,AAV9载体处理的动物中的NfL值更高。然而,在AAV9载体和载体给药的动物之间评估的三个功能终点没有显着差异，或在基线（给药前）之间的纵向比较中，AAV9载体-剂量动物中的4和8周值。这些发现表明，我们的AAV9载体治疗在大鼠中观察到的最小至中度神经变性没有可检测的功能后果，提示在全身施用AAV9载体后DRG神经元的功能耐受性或保留。
