生物学 神经科学 全文翻译
2021-03-16 17:33:01

CRISPR-based gene therapy dampens pain in mice


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


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.



“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.



A new way to target pain


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.


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.


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


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


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.



Harnessing CRISPR’s precision


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.


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.



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.


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。










上一篇: PDF文档怎么翻译?学会这个教程一步秒翻
下一篇: 肠道菌群重组以帮助感染后防御