CRISPR-based gene therapy dampens pain in mice

基于CRISPR的基因疗法可减轻小鼠疼痛

Targeted approach could lead to an opioid-free way of treating chronic pain.

有针对性的方法可能会导致无阿片类药物治疗慢性疼痛。

Ariana Remmel

阿丽亚娜·雷梅尔（Ariana Remmel）

Pain signals are transmitted to the brain through neurons similar to these in the spinal cord.Credit: Jose Calvo/Science Photo Library

疼痛信号通过类似于脊髓中的神经元传递到大脑。图片来源：Jose Calvo /科学图片库

A gene-silencing technique based on CRISPR can relieve pain in mice, according to a study1. Although the therapy is still a long way from being used in humans, scientists say it is a promising approach for squelching chronic pain that lasts for months or years. Chronic pain is typically treated with opioids such as morphine, which can lead to addiction.

一项研究表明，基于CRISPR的基因沉默技术可以减轻小鼠的疼痛。尽管该疗法距离人类使用还有很长的路要走，但科学家们说，这是消除持续数月或数年的慢性疼痛的一种有前途的方法。慢性疼痛通常用阿片类药物（如吗啡）治疗，这可能会导致成瘾。

“It’s a real challenge that the best drugs we have to treat pain give us another disease,” says Margarita Calvo, a pain physician at the Pontifical Catholic University of Chile, in Santiago, who wasn’t involved in the research. That’s why the CRISPR-based technique is exciting, she says.

圣地亚哥的智利天主教大学的止痛医生玛格丽塔·卡尔沃（Margarita Calvo）表示：“这是一个真正的挑战，我们必须使用最佳的药物来治疗疼痛，这会给我们带来另一种疾病。”她说，这就是基于CRISPR的技术令人兴奋的原因。

Scientists are already evaluating CRISPR therapies that edit a person’s genome as treatments for blood diseases and some forms of hereditary blindness. The new version of CRISPR doesn’t edit genes directly — it stops them from being expressed — and so shouldn’t cause permanent changes, although it’s unclear how long its effects last for.

科学家已经在评估可编辑人基因组的CRISPR疗法，以治疗血液疾病和某些形式的遗传性失明。新版本的CRISPR不能直接编辑基因-它阻止了基因的表达-因此不应造成永久性改变，尽管目前尚不清楚其作用能持续多长时间。

A new way to target pain

针对疼痛的新方法

Some studies estimate that a large proportion of the population in Europe and the United States — as high as 50% — experiences chronic pain2,3. This pain can become debilitating over time by limiting a person’s activity and having a negative effect on their mental health. Despite the prevalence of the condition, few options exist for providing long-term relief without side effects. Even so, doctors have been moving away from prescribing opioids owing to addiction risk, and that has pared down their options even further.

一些研究估计，欧洲和美国的大部分人口（高达50％）都患有慢性疼痛2,3。随着时间的流逝，这种疼痛可能会因限制人的活动并对其心理健康产生负面影响而变得虚弱。尽管该病很普遍，但提供长期缓解而又没有副作用的选择很少。即便如此，由于成瘾的风险，医生已经不再开处方阿片类药物，这进一步削减了他们的选择范围。

This plight inspired bioengineer Ana Moreno and colleagues at the University of California, San Diego, to seek an alternative treatment.

这种困境激发了加利福尼亚大学圣地亚哥分校的生物工程师Ana Moreno及其同事的灵感，寻求替代疗法。

Pain registers with the brain when a stimulus — such as touching a scalding hot pan or being poked with a sharp object — triggers neurons to send an electrical signal through the nerves in the spinal cord and upwards to the brain. This happens when pore-like openings along the neuron — called ion channels — open and close to allow ions to pass through, which transmits a current along the nerve. With chronic pain, parts of this pathway can become hyperactive.

当刺激（例如触摸烫伤的锅或用锋利的物体戳戳）刺激大脑触发神经元，使其通过脊髓中的神经向大脑发送电信号时，疼痛就会在大脑中出现。当沿着神经元的毛孔状开口（称为离子通道）打开和关闭以允许离子通过时，就会发生这种情况，离子沿着神经传递电流。如果患有慢性疼痛，该途径的某些部分可能会变得过度活跃。

Although there are many types of ion channel, studies have suggested that a sodium channel called Nav1.7 could play a central part in chronic pain. When

尽管离子通道的类型很多，但研究表明，一个名为Nav1.7的钠通道可能在慢性疼痛中起着中心作用。什么时候

people have mutations in the gene coding for this channel, they either experience extreme, constant pain, or can’t feel any pain at all.

人们在编码该通道的基因中发生了突变，他们要么经历着持续不断的痛苦，要么根本没有任何痛苦。

So Moreno and her team thought they might be able to stop pain signals travelling to the brain by preventing neurons from producing Nav1.7. Chemists have been trying to block Nav1.7 with small-molecule drugs and antibodies, but have struggled because these therapies also interact with structurally similar sodium channels in the body, causing side effects including numbness and poor coordination. But with CRISPR, which targets genes with precision, the researchers thought they might be able to hit Nav1.7 directly, without any off-target effects.

因此，莫雷诺和她的团队认为，通过阻止神经元产生Nav1.7，他们也许能够阻止疼痛信号传播到大脑。化学家一直在试图用小分子药物和抗体来阻断Nav1.7，但由于这些疗法还与体内结构相似的钠通道相互作用而产生了苦恼，导致副作用，包括麻木和协调性差。但是，利用精确定位基因的CRISPR，研究人员认为它们可能能够直接击中Nav1.7，而不会产生脱靶效应。

Harnessing CRISPR’s precision

利用CRISPR的精度

The team started with a modified version of the Cas9 protein that’s normally part of the CRISPR gene-editing system. It could target, but not cut, the DNA sequence encoding Nav1.7. The researchers attached to the modified Cas9 a second, ‘repressor’ protein that stops the Nav1.7 gene from being expressed. The researchers packaged this system in a small, inactive virus called an adeno-associated virus that could shuttle it into cells.

研究小组从Cas9蛋白的改良版开始，该蛋白通常是CRISPR基因编辑系统的一部分。它可以靶向但不能切割编码Nav1.7的DNA序列。研究人员在修饰的Cas9上附加了第二个“阻遏”蛋白，从而阻止了Nav1.7基因的表达。研究人员将该系统包装在一种称为腺相关病毒的小型无活性病毒中，该病毒可以将其穿梭到细胞中。

They gave mice a spinal injection of the gene-silencing therapy, then tried to induce chronic pain by injecting the animals with chemotherapy drugs or inflammatory agents. These mice were more tolerant of painful stimuli. And mice that were already suffering from chronic pain benefited from the therapy, the team showed. For instance, mice that received doses of chemotherapy became very sensitive to pain, but lost that sensitivity after a single injection of the gene therapy. The results were published in Science Translational Medicine on 10 March1.

他们给小鼠进行了基因沉默疗法的脊髓注射，然后试图通过给动物注射化学疗法药物或炎症剂来诱发慢性疼痛。这些小鼠对疼痛刺激更宽容。研究小组表明，已经患有慢性疼痛的小鼠也从这种疗法中受益。例如，接受化学疗法剂量的小鼠对疼痛变得非常敏感，但是在单次注射基因治疗后就失去了这种敏感性。研究结果于1月10日发表在《科学转化医学》上。

The pain relief seemed to last, in some cases, for as long as 44 weeks after the injection. “That’s quite remarkable,” says Sulayman Dib-Hajj, a neuroscientist at Yale University in New Haven, Connecticut.

在某些情况下，注射后疼痛缓解可能持续长达44周。 “这非常了不起，”康涅狄格州纽黑文市耶鲁大学的神经科学家Sulayman Dib-Hajj说。

Importantly, says Calvo, the treatment seems to have knocked down expression of Nav1.7 without shutting down other sodium channels — the mice didn’t lose any sensations apart from pain, and displayed no other side effects.

卡尔沃说，重要的是，这种疗法似乎在不关闭其他钠通道的情况下敲低了Nav1.7的表达-小鼠除疼痛外没有失去任何感觉，也没有表现出其他副作用。

Despite their excitement, scientists caution that these results are still preliminary, and they don’t know whether the pain relief observed in mice will translate to humans. “It gives us hope that gene-therapy approaches may work in humans” for treating chronic pain, says Dib-Hajj, “but more work needs to be done.”

尽管很兴奋，科学家们警告说，这些结果仍是初步的，他们不知道在小鼠中观察到的疼痛缓解是否会转化为人类。 Dib-Hajj说：“它给我们希望基因治疗方法可能对人类有用”，以治疗慢性疼痛，“但还需要做更多的工作。”

Moreno is now chief executive of Navega Therapeutics in San Diego, which plans to continue developing the treatment with the hope of one day trialling it in humans.

莫雷诺现在是圣地亚哥Navega Therapeutics的首席执行官，该公司计划继续开发这种疗法，希望有一天能在人体中进行试验。

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来源于：nature