A new player in gene therapy for pain?
A new player in gene therapy for pain?
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DOI：
10.1038/gt.2008.80
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发表时间：
2008-05
期刊：
影响因子：
5.1
通讯作者：
M. Pohl;D. Fink
中科院分区：
文献类型：
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作者：
M. Pohl;D. Fink
在最近的一份引起大众媒体注意的报告中，Beutler和同事1提出了证据，即鞘内接种携带编码前β-内啡肽原的序列的血清型8的基于腺相关病毒（AAV）的载体减少了神经性疼痛的脊神经结扎模型中的机械性异常性疼痛。慢性疼痛，特别是由周围神经损伤引起的神经性疼痛，是一个严重的问题，通常是最好的常规治疗方法难以治愈的。2过去几十年的进展为急性疼痛感知（伤害感受）的解剖学、生理学和分子生物学以及许多导致向慢性疼痛状态过渡的改变提供了实质性的见解。3，4但是由于神经系统中疼痛和非疼痛通路中使用的离子通道、神经递质和神经递质受体的库有限，因此很难识别选择性靶向疼痛相关通路的小分子。常规镇痛剂（例如吗啡）的鞘内递送已经使用了一段时间，以通过将最高浓度的药物物理地引导至脊髓来增强药物的疼痛缓解效力。在这里，背根神经节（DRG）的伤害性神经元末梢和脊髓中的二级神经元之间的疼痛通路中的第一突触提供了一个有吸引力的靶点来调节疼痛神经传递。使用基因转移代替药物递送来实现脊髓背角内或附近持续释放短寿命生物活性肽是疼痛基因治疗最常见策略的基础。有两种主要模式。第一种涉及鞘内注射来源于腺病毒、AAV或脂质包封质粒的载体。两者都表现出强大的抗异常性疼痛和抗痛觉过敏作用，在两次注射编码白细胞介素-10的质粒后显示出延长的作用。5.已知由注射到脑脊液中的载体转导的细胞包括排列在鞘内空间中的驻留脑膜细胞以及脊髓实质中的神经元和神经胶质。在第二种方法中，通过将单纯疱疹病毒载体注射到皮肤中来转导DRG的神经元。这些天然亲神经性载体通过逆行轴突运输从皮肤携带到DRG的神经元核周体。在这里，它们影响抑制性神经递质6或抗炎肽7的产生，以减轻几种不同慢性疼痛8模型的疼痛。本报告介绍了一种修改后的方法，该方法结合了上述每种方法的特点。近年来，已经从人或灵长类动物组织中分离出几种新的血清型，包括AAV血清型7、8和9以及超过100种其他AAV变体作为DNA序列，其中几种变体显示出不同的组织向性。在目前的报告中，Beutler和同事证明鞘内注射含有绿色荧光蛋白报告基因转基因的血清型8 AAV导致转导到DRG神经元中。背根神经节位于神经根袖的末端，神经根袖与鞘内空间相连，因此被脑脊液浸泡。但血清型8 AAV对DRG神经元的感染显然是独特的;例如，血清型2 AAV在通过相同途径施用时不感染DRG神经元。含有前probeta-内啡肽基因的血清型8 AAV载体的抗异常性疼痛作用的幅度似乎与其他基因转移方法所实现的效果相当，并且疼痛缓解的持续时间比通过基因转移方法所实现的更长。
In a recent report that has garnered notice by the popular press, Beutler and co-workers 1 present evidence that intrathecal inoculation of an adeno-associated virus (AAV)-based vector of serotype 8 carrying a sequence coding for prepro-beta-endorphin reduces mechanical allodynia in the spinal nerve ligation model of neuropathic pain. Chronic pain, particularly neuropathic pain arising from damage to peripheral nerves, is a serious problem that is often refractory to the best available conventional therapies. 2 Advances over the past decades have provided substantial insight into the anatomy, physiology and molecular biology of acute pain perception (nociception) and many of the alterations responsible for the transition to chronic pain states. 3, 4 But because a limited repertoire of ion channels, neurotransmitters and neurotransmitter receptors are employed in pain and nonpain pathways in the nervous system, it has been difficult to identify small molecules that selectively target pain-related pathways. Intrathecal delivery of conventional analgesic agents (for example, morphine) has been used for some time to enhance the pain-relieving potency of drugs by physically directing the drug in highest concentration to the spinal cord. Here, the first synapse in the pain pathway between nociceptive neurons terminals of the dorsal root ganglion (DRG) and second order neurons in the spinal cord provide an attractive target to modulate pain neurotransmission. The use of gene transfer, in place of drug delivery to achieve the continuous release of short-lived bioactive peptides in or near the spinal dorsal horn underlies the most common strategies for gene therapy of pain. There are two principal models. The first involves intrathecal injection of vectors derived from adenovirus, AAV or lipid encapsulated plasmids. Both have demonstrated robust antiallodynic and antihyperalgesic effects, with prolonged effects shown after two injections of a plasmid coding interleukin-10. 5 The cells transduced by vectors injected into the cerebrospinal fluid are known to include resident meningeal cells lining the intrathecal space as well as neurons and glia in spinal parenchyma. In the second approach, neurons of the DRG are transduced by injection of herpes simplex virus-based vectors into the skin. These naturally neurotropic vectors are carried by retrograde axonal transport from the skin to the neuronal perikaryon of the DRG. Here they effect production of inhibitory neurotransmitters 6 or anti-inflammatory peptides 7 to reduce pain in several different chronic pain 8 models. The current report describes a modified method that incorporates features from each of these approaches. In recent years, several novel serotypes including AAV serotypes 7, 8 and 9 and more than 100 other AAV variants have been isolated as DNA sequences from human or primate tissues, 9 with several of these variants showing distinct tissue tropisms. In the current report, Beutler and colleagues demonstrate that intrathecal injection of a serotype 8 AAV containing a green fluorescent protein reporter transgene results in transduction into DRG neurons. The DRG lies physically at the end of root sleeves, which are continuous with the intrathecal space and, thus, bathed by cerebrospinal fluid. But infection of DRG neurons by serotype 8 AAV is apparently unique; serotype 2 AAV, for example, does not infect DRG neurons when administered by the same route. The magnitude of the antiallodynic effect of serotype 8 AAV vector containing the preprobeta-endorphin gene appears to be comparable to that achieved by other gene transfer methods, and the duration of pain relief is longer than that achieved by a …