An Adeno-Associated Viral vector encoding Neurotrophin 3 injected into affected forelimb muscles modestly improves sensorimotor function after contusive mid-cervical spinal cord injury
An Adeno-Associated Viral vector encoding Neurotrophin 3 injected into affected forelimb muscles modestly improves sensorimotor function after contusive mid-cervical spinal cord injury
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DOI：
10.1101/2021.02.24.432676
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发表时间：
2021-02
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影响因子：
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通讯作者：
Jared D. Sydney Smith;Vanessa Megaro;A. B. Spejo;L. Moon
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作者：
Jared D. Sydney Smith;Vanessa Megaro;A. B. Spejo;L. Moon
人类的创伤性脊髓损伤（SCI）最常发生在颈椎，在那里它可以导致上肢功能的实质性感觉运动障碍。改变的输入到病变下方的脊髓回路导致适应不良的重组，这通常导致本体感受回路的反射亢进。神经营养因子3（NT 3）是本体感受神经元发育所必需的生长因子。我们先前已经表明，双侧皮质脊髓束轴突切断术后，肌肉内递送编码NT 3的腺相关病毒载体（AAV-NT 3）诱导与功能恢复相关的本体感受回路重组。为了评估其在大鼠中临床相关的双侧C5-C6挫伤后的治疗效果，在损伤后24小时将AAV-NT 3肌内注射到优势肢中，并在13周内评估前肢功能。损伤产生了远侧前肢本体感受回路的反射亢进。在伸手抓握和在水平梯子上行走时，也有精细运动技能的丧失。离体磁共振成像（MRI）显示脊髓萎缩和整个病变部位的白色物质破坏以及广泛的灰质损失。出乎意料的是，与PBS处理的动物相比，用AAV-NT 3处理的动物在靠近震中的区域中具有略小的病变。用AAV-NT 3处理的大鼠在水平梯上表现出微妙的更好的表现，并且在达到和抓握上表现出短暂的益处。AAV-NT 3没有使治疗的肌肉中的反射亢进正常化。该处理增加了经处理的肌肉中NT 3的量，但出乎意料的是，血清水平仅在一小部分动物中升高。这些结果表明，AAV-NT 3的这种剂量和递送可以产生运动的细微改善，但需要额外的治疗来克服由挫伤引起的广泛的感觉运动缺陷。
Traumatic spinal cord injury (SCI) in humans occurs most frequently in the cervical spine where it can cause substantial sensorimotor impairments to upper limb function. The altered input to spinal circuits below the lesion leads to maladaptive reorganisation which often leads to hyperreflexia in proprioceptive circuits. Neurotrophin 3 (NT3) is growth factor essential for the development of proprioceptive neurons. We have previously shown that following bilateral corticospinal tract axotomy, intramuscular delivery of an Adeno-Associated Viral vector encoding NT3 (AAV-NT3) induces proprioceptive circuit reorganisation linked to functional recovery. To assess its therapeutic effects following a clinically relevant bilateral C5-C6 contusion in rats, AAV-NT3 was injected intramuscularly into the dominant limb 24 hours after injury and forelimb function was assessed over 13 weeks. The injury generated hyperreflexia of a distal forelimb proprioceptive circuit. There was also loss of fine motor skills during reach-and-grasp and walking on a horizontal ladder. Ex vivo magnetic resonance imaging (MRI) revealed atrophy of the spinal cord and white matter disruption throughout the lesion site together with extensive loss of grey matter. Unexpectedly, animals treated with AAV-NT3 had a slightly smaller lesion in the regions close to the epicentre compared to PBS treated animals. Rats treated with AAV-NT3 showed subtly better performance on the horizontal ladder and transient benefits on reach-and-grasp. AAV-NT3 did not normalise hyperreflexia in a treated muscle. The treatment increased the amount of NT3 in treated muscles but, unexpectedly, serum levels were only elevated in a small subset of animals. These results show that this dose and delivery of AAV-NT3 may generate subtle improvements in locomotion but additional treatments will be required to overcome the widespread sensorimotor deficits caused by contusion injury.