Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair
Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair
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DOI：
10.1016/j.expneurol.2021.113945
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发表时间：
2021-12
影响因子：
5.3
通讯作者：
Jared D Sydney-Smith;A. B. Spejo;P. Warren;L. Moon
中科院分区：
文献类型：
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作者：
Jared D Sydney-Smith;A. B. Spejo;P. Warren;L. Moon
通过外周和自主神经系统，脊髓直接或间接地与许多身体系统（肌肉，integumentary，呼吸，免疫，消化，排泄，生殖，心血管等）相连。因此，脊髓损伤（SCI）可导致多个身体系统的灾难，包括影响运动的肌肉麻痹和正常感觉的丧失，以及神经性疼痛、痉挛、生育能力降低和自主反射障碍。脊髓损伤的治疗和治愈可能需要治疗剂穿过血液-CNS（中枢神经系统）屏障。然而，CNS内的某些类型的修复可能通过靶向治疗至位于外周的细胞或通过外周途径递送腺相关病毒载体（AAV）（例如，鞘内、静脉内）。这篇综述将考虑一些未来的可能性脊髓损伤修复产生的治疗外周基因传递。目前，全世界有六种基因疗法被批准为安全有效的药物，其中三种是通过修饰明显无致病性的腺相关病毒而产生的。这些AAV之一Zolgensma鞘内注射用于治疗儿童脊髓性肌萎缩症。有一天，将AAV递送到外周组织中可能会改善人类脊髓损伤后的恢复;我们讨论了我们和其他人在SCI或中风动物模型中将转基因递送到神经或肌肉中用于感觉运动恢复的实验，包括人神经营养素-3。我们还描述了正在进行的开发AAV的努力，所述AAV在外周施用后使用具有改善的向性的衣壳、对特定细胞类型具有选择性的启动子以及用于控制转基因表达的剂量和持续时间的方法递送至CNS内和CNS外的特定靶标。总之，在未来，AAV的微创给药可能会改善SCI后的恢复，副作用最小。
Via the peripheral and autonomic nervous systems, the spinal cord directly or indirectly connects reciprocally with many body systems (muscular, intengumentary, respiratory, immune, digestive, excretory, reproductive, cardiovascular, etc). Accordingly, spinal cord injury (SCI) can result in catastrophe for multiple body systems including muscle paralysis affecting movement and loss of normal sensation, as well as neuropathic pain, spasticity, reduced fertility and autonomic dysreflexia. Treatments and cure for an injured spinal cord will likely require access of therapeutic agents across the blood-CNS (central nervous system) barrier. However, some types of repair within the CNS may be possible by targeting treatment to peripherally located cells or by delivering Adeno-Associated Viral vectors (AAVs) by peripheral routes (e.g., intrathecal, intravenous). This review will consider some future possibilities for SCI repair generated by therapeutic peripheral gene delivery. There are now six gene therapies approved worldwide as safe and effective medicines of which three were created by modification of the apparently nonpathogenic Adeno-Associated Virus. One of these AAVs, Zolgensma, is injected intrathecally for treatment of spinal muscular atrophy in children. One day, delivery of AAVs into peripheral tissues might improve recovery after spinal cord injury in humans; we discuss experiments by us and others delivering transgenes into nerves or muscles for sensorimotor recovery in animal models of SCI or of stroke including human Neurotrophin-3. We also describe ongoing efforts to develop AAVs that are delivered to particular targets within and without the CNS after peripheral administration using capsids with improved tropisms, promoters that are selective for particular cell types, and methods for controlling the dose and duration of expression of a transgene. In conclusion, in the future, minimally invasive administration of AAVs may improve recovery after SCI with minimal side effects.