20240806|基因编辑加速迈向临床应用（下）

The disorder, which affects one in 250 people, results in reduced clearance of bad cholesterol from the blood.

每250人中就有1人患这种病，会导致血液中坏胆固醇的清除率降低。

The treatment, VERVE-101, made by Verve Therapeutics, turns off the PCSK9 gene in the liver by making a single-letter change in the DNA (from A to G).

由Verve Therapeutics研发的这种治疗方法是VERVE-101，它通过对DNA进行单字母改变（从A变为G）来关闭肝脏中的PCSK9基因。

Beam Therapeutics, based in Cambridge, Massachusetts, is using base editing to make therapies for a range of conditions.

总部位于马萨诸塞州剑桥的Beam Therapeutics正在使用碱基编辑来治疗一系列疾病。

These include making four DNA-letter changes to immune cells so that they are better able to attack leukaemia, as well as a product that works for the same diseases as Casgevy.

其中包括对免疫细胞进行四个DNA字母的改变，以便它们能够更好地对抗白血病，以及一种适用于与Casgevy相同疾病的产品。

The company reckons its base-editing drug will work better than CRISPR-Cas9 and deliver higher levels of haemoglobin.

该公司认为其碱基编辑药物的效果将优于CRISPR-Cas9，并提供更高水平的血红蛋白。

Data from early trials of base-editing technology in patients are expected in the second half of this year.

预计今年下半年将获得碱基编辑技术在患者中的早期试验数据。

At the clinical frontier is "prime editing", which uses a Cas9 nickase along with a specially designed RNA guide that not only locates the correct region of DNA, but also carries a template of the desired change.

临床前沿是“prime editing”，它使用Cas9切口酶和专门设计的RNA向导，不仅可以定位正确的DNA区域，还可以携带所需改变的模板。

Also attached to the CRISPR protein is an enzyme called reverse transcriptase.

CRISPR蛋白上还附着逆转录酶。

This reads the RNA template and synthesises the correct DNA sequence at the location of the nicked site, giving a precisely edited gene.

它读取RNA模板并在切口位置合成正确的DNA序列，从而产生精确编辑的基因。

In April David Liu, a molecular biologist at Harvard University, posted on X that the first trial to use prime editing in a patient had been approved only four and a half years after his lab had published the first paper on the technology.

4 月，哈佛大学分子生物学家刘如谦在X上发帖称，在他的实验室发表第一篇关于该技术的论文仅仅四年半之后，首次在患者身上使用prime editing的试验就已获得批准。

Prime Medicine, a biotech firm in Cambridge, Massachusetts, has already begun clinical trials of its drug PM359 for the treatment of chronic granulomatous disease-a life-threatening condition that affects the blood's ability to destroy infections.

马萨诸塞州剑桥的一家生物技术公司Prime Medicine已经开始对其药物PM359进行临床试验，用于治疗危及生命的慢性肉芽肿病，此病会影响血液消灭感染的能力。

Being able to change larger pieces of the genome, as is the case with prime editing, makes it possible to treat diseases where errors stretch over a long distance, like Huntington's disease.

像prime editing一样，PM359能够改变较大的基因组片段，这使得治疗错误延伸到很远距离的疾病成为可能，比如亨廷顿氏病。

But it could also help with the tricky economics of treating rare diseases.

但它也可以帮助解决治疗罕见疾病的棘手经济问题。

Instead of making a medicine that treats a single mutation to a gene, it would be possible to fix many types of mutation with one correction.

无需制造一种治疗基因单一突变的药物，只需一次校正即可修复多种类型的突变。

The flexibility of the technology means that, in theory, prime editing could correct almost 90% of disease-causing genetic variations.

该技术十分灵活，理论上，prime editing可以纠正近90%的致病遗传变异。

The technological progress in gene-editing tools has not stopped.

基因编辑工具的技术进步并未停止。

Yet another method, known as "bridge RNA", details of which were published in Naturein June, uses a form of guide RNA that recognises two stretches of DNA-the target site and the new gene that is to be inserted.

还有一种方法被称为“桥接RNA”，其细节于6月发表在《自然》杂志上，它使用一种向导RNA，可以识别两段DNA——目标位点和要插入的新基因。

This new technique allows large stretches of DNA to be added, removed or inverted. All these new technologies face technical and safety hurdles in the years ahead.

这项新技术允许添加、移除或反转大段DNA。所有这些新技术在未来几年都面临技术和安全障碍。

A big question is how to deliver therapies to the right place in the body. Blood cells, cancers, the retina and the liver are all easy to reach and edit. The brain and lungs are more difficult.

一个大问题是如何将疗法输送到身体的正确位置。血细胞、癌症、视网膜和肝脏都很容易到达和编辑。大脑和肺部更难。

One solution to the delivery problem, proposed by Aera Therapeutics of Cambridge, Massachusetts, is a capsid, a nanoparticle with a protein shell.

马萨诸塞州剑桥的Aera Therapeutics公司提出了一种解决输送问题的方法，即使用衣壳，即带有蛋白质外壳的纳米颗粒。

Based on human proteins, these nanoparticles could be targeted to different tissues while also not provoking a strong response from the body's immune system.

这些纳米颗粒以人类蛋白质为基础，可以针对不同的组织，同时不会引起人体免疫系统的强烈反应。

But perhaps the biggest challenge will be economic. So far, the new generation of genomic medicines have been eye-wateringly expensive-a shot of Hemgenix, a haemophilia B gene-therapy, costs $3.5 million, around a million dollars more than Casgevy.

但最大的挑战或许是经济问题。到目前为止，新一代基因组药物的价格高得令人咋舌——一剂Hemgenix（一种血友病B基因疗法）的价格为350万美元，比Casgevy贵了大约100万美元。

Firms believe they can charge high prices not only because of the costs of developing and making the drugs, but because they offer potentially lifelong benefits (although the durability of these treatments remains to be proved).

公司认为，他们之所以能收取高价，不仅是因为开发和制造药物的成本，还因为它们可能带来终身益处（尽管这些治疗的持久性仍有待证实）。

There are reasons to think costs might come down in time. Treating diseases that affect larger patient groups, such as heart disease, would help reduce costs.

有理由认为成本可能会随着时间的推移而下降。治疗影响更大患者群体的疾病（如心脏病）将有助于降低成本。

Ultimately, many believe gene-editing tools will evolve into "platforms", where the core technology would remain unchanged and only the specific instructions for changing genes would be tweaked for new diseases.

最终，许多人相信基因编辑工具将演变成“平台”，其中核心技术将保持不变，只有改变基因的具体指令会针对新疾病进行调整。

This would reduce the need for clinical trials for every new drug.

这将减少每种新药进行临床试验的需要。

Until that happens, though, firms may be forced to drop even promising treatments because of market conditions.

然而，在此之前，公司可能会因为市场状况而被迫放弃甚至有希望的治疗方法。

Yet gene editing is moving so fast that it seems only a question of when, not if, these new medicines will overcome their difficulties.

然而，基因编辑的发展如此之快，这些新药克服困难似乎只是一个时间问题，而不是是否能克服的问题。