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阿尔茨海默病的曙光

An Alzheimer’s Drug That Doesn’t Treat Alzheimer’s?

Thanks to Linode Cloud Computing for supporting this episode of SciShow.
感谢Linode云计算赞助本期《科学秀》
Head to linode.com/scishow to learn more and get a $100 60-day credit
登录linode·com 或scishow了解更多及获得新账号
on the new linode account
100美元60天的信用
[♪ INTRO]
前奏
There’s a big new Alzheimer’s treatment on the block.
市面上出现了一种大型新阿尔茨海默病疗法
It’s the first drug approved by the FDA here in the US that claims to stop
这被美国食品药品监督管理局首次批准的药物 宣称
Alzheimer’s at the source, by removing the plaques that cause disease.
可以通过移除淀粉样斑块 从根源上阻断阿尔茨海默病
This new drug, aducanumab, is the first of its kind.
阿杜那单抗这种新型的药物是同类中首次被批准的
It’s designed to stick to and help clear the amyloid plaques in the brain
它的目标是靶向并清除大脑中的淀粉样蛋白斑块
long thought to cause the symptoms of Alzheimer’s disease.
而淀粉样斑块一直被认为是阿尔茨海默病症状的起因
But there’s a problem.
但有个问题
The biomarkers of a disease, like amyloid plaques,
一种疾病的生物标志物 比如说淀粉样蛋白斑块
are meant to be objective measures of that disease.
要公认是评估对应疾病的客观标准
And they seem like they should go hand in hand with its clinical symptoms.
且它们似乎也应该跟临床症状息息相关
But they don’t always.
但事实不总这样
And understanding that might make a big difference for how we approach
理解了这点可能会极大改善
Alzheimer’s treatments going forward.
未来对阿尔茨海默病的治疗方法
People with Alzheimer’s disease have buildups of protein in their brains,
阿尔茨海默病患者的大脑中积累了蛋白质
consisting of two main types:
这些蛋白质 主要包括两种类型
tangles of tau within cells, and of amyloid-beta outside of cells.
细胞内的tau蛋白缠结和细胞外的β—淀粉样蛋白缠结
That amyloid-beta accumulates into plaques.
β—淀粉样蛋白积累形成斑块
Aducanumab was designed to lock onto amyloid plaques
阿杜那单抗目标是锁定淀粉样蛋白
and help the immune system identify and remove them.
且帮助免疫系统识别并移除它们
This was all in line with the dominant theory of what causes Alzheimer’s disease:
这全都符合阿尔茨海默病最著名的致病理论即:
the amyloid hypothesis.
淀粉样蛋白假说
Basically, scientists saw those plaques accumulating in those with Alzheimer’s
说白了 科学家们看到淀粉样斑块在阿尔茨海默病者大脑中聚集
and concluded that that’s probably…
并得出结论:
not what should be happening.
那不该发生的
In the 80s and 90s, scientists discovered that amyloid-beta is a chopped down
在80年代和90年代 科学家们发现β—淀粉样蛋白是
version of a larger protein, known as amyloid precursor protein or APP.
一种更大蛋白质的精简版 被称为淀粉样前体蛋白或者APP
And later, they came across the enzymes that do the chopping:
随后 它们遇到发挥切割作用的酶:
β-secretase and γ-secretase.
β—分泌酶和γ—分泌酶
But the amyloid hypothesis really got legs when scientists discovered that genetics
但当科学家发现了 跟这些酶有关的遗传学 对一种遗传性阿尔茨海默病
relating to these enzymes played a big role in one type of inheritable Alzheimer’s.
有很大作用时 淀粉样蛋白假说才真正变得有据可依
Alzheimer’s most often develops in people with no family history of the disease.
阿尔茨海默病最常发病在没有这种家族遗传病史的人身上
But some cases have a strong genetic component,
但是一些案例具有很强的遗传因素
and identifying those genes should help us understand the causes of Alzheimer’s.
识别这些基因应该有助于我们了解阿尔茨海默病的起因
In the 90s, researchers pinpointed PSEN1 and PSEN2.
在90年代 研究人员精确指出了PSEN1和PSEN2 两种多通道膜蛋白
These genes affect where the secretases cut APP,
这些基因在分泌酶剪切淀粉样前体蛋白时发挥作用
which determines the length of the amyloid-beta fragments.
而这决定了β—淀粉样蛋白的片段长度
That finding was super important, because longer lengths of amyloid-beta
这项结果极其重要 因为β—淀粉样蛋白越长
clump together a lot more easily.
就越容易集结在一起
And the easier they clump, the more readily amyloid plaques form.
而β—淀粉样蛋白越容易集结 淀粉样蛋白斑块就越容易形成
Scientists were able to see plaques forming in people
科学家们能够看到斑块在人们脑中形成
with variants of PSEN1 and 2 that favor long amyloid-beta.
这些人携带 利于长段β—淀粉样蛋白的PSEN1和PSEN2
Those same gene variants were seen in people with familial Alzheimer’s.
在家族性的阿尔茨海默病者脑中发现了相同的基因病变体
Because of that, researchers felt like there was a really good case
正因如此 研究人员感觉有个非常棒的论据
for amyloid being the culprit in causing Alzheimer’s.
证明淀粉样蛋白即造成阿尔茨海默病的罪魁祸首
If that hypothesis is correct, then if we could take those plaques out,
如果假说是正确的 倘若我们能够取出那些斑块
we should have a cure, right?
阿尔茨海默病不就被治愈了吗?
Well, unfortunately…
然而 不幸的是
the results of our massive effort to cure Alzheimer’s
我们付出大量努力消除淀粉样蛋白去治疗
by treating amyloid have fallen very flat.
阿尔茨海默病患者 结果却是一败涂地
One meta-analysis, published in 2021, pooled data from
一篇2021年发表的元分析理论
14 randomized controlled trials to look for evidence that drugs
集中了14组随机对照的实验数据 这些实验寻找证据
which reduced amyloid plaques also improved cognition in participants.
证明这些减少淀粉样蛋白斑块的药物 也改善了参与者的认知
Amyloid plaques are a key biomarker of Alzheimer’s.
淀粉样蛋白斑块是阿尔茨海默病的关键生物标志物
That can be a broad term, but in this case, it’s basically something we can measure
那可能是个广泛的术语 但它是与这种疾病有关的
objectively that’s associated with the disease,
我们能够客观测量的生物标志
which is often very useful in clinical trials.
其通常在临床试验上非常有帮助
But!
但是!
If you clear away a biomarker, but it doesn’t actually help patients,
如果你清除掉一个生物标志物 然而没有实际帮到患者
you’re not curing the disease at all.
那你根本就没治愈这种病
Which is why a drug that affects a biomarker
这就是为什么一种对生物标志物起作用的药物
also needs to affect the clinical signs of the disease,
还需要对这种病的临床症状起作用
and improve how people actually feel or decrease their need for medical care.
且能改善患者实际感受或者降低他们对医疗保健的需求
In medical parlance, it needs to improve patient outcomes.
用医疗术语说 要提高患者成效
Taken together, the data from all trials showed that those given
总而言之 所有试验数据表明
the amyloid-targeting treatments didn’t experience any significant improvements
靶向淀粉样蛋白的治疗对患者的认知症状
in their cognitive symptoms.
没有任何显著改善
Which is part of what makes the approval of a new drug
这也是让仅靶向斑块的新型药物
targeting just plaques kind of bizarre.
获得了批准有点荒诞的部分
If there’s evidence targeting amyloid in various ways doesn’t seem to make a
如果有证据表明 靶向淀粉样蛋白通过各种途径似乎都不起作用
difference, why are we licensing a drug that does just that as a treatment?
那为何我们还要许可 如此没有疗效的治疗药物呢?
This is the part of the episode where I should be able to pull out the stats
本集的这部分 我应该撇开
from aducanumab’s clinical trial and argue
阿杜那单抗的临床试验数据
that it had some effect on cognitive symptoms.
讨论其对认知症状的某些影响
But in fact, I’m going to do the exact opposite!
但事实上 我要做的完全相反
The team conducting these trials didn’t post any data
组织这些试验的团队没有公布任何数据
suggesting that it improved cognitive symptoms in Alzheimer’s patients.
表明它能改善阿尔茨海默患者的认知症状
The phase three trials for aducanumab were actually stopped prematurely
2019年3月针对阿杜那单抗的三期试验
in March 2019.
事实上都被过早地结束了
That’s the biggest and last phase of human trials
那三期实验是同类药物被提交认证之前
before a drug is submitted for approval.
最后规模最大的人类研究实验阶段
The trials were stopped because data indicated that the drug
试验被结束是因为数据表明
wasn’t going to meet its goals of improving Alzheimer’s symptoms.
这种药物并不能达到改善阿尔茨海默症状的目标
At the time, one trial was trending positive, just not enough.
当时 其中一个实验结果趋向积极 但还不够
The other showed no statistical benefits.
而其他的也没有统计上的成效
They did, however, demonstrate a reduction in what was considered
然而他们的确证明了被看作关键
a key biomarker: the amount of amyloid plaque.
生物标志物的淀粉样蛋白斑块数量的减少
Just not clinically meaningful endpoints, like symptom reduction.
却不是临床意义上的终点 比如症状的减少
And, that’s where the phase three research ended.
那正是三期研究被结束的地方
On a cliff-hanger.
结果悬而未知
Despite this, in 2021 the FDA approved aducanumab anyway,
尽管如此 2021年美国食品药品监督局还是通过
via its Accelerated Approval Pathway.
其加速批准通道批准了阿杜那单抗
This means a license was granted based on a drug’s effect on biomarkers,
这意味着 根据药物对生物标志物的作用
rather than actual improvements in symptoms of cognitive decline.
而不是对认知障碍症状的实际改善 授予了许可证
We won’t get into it too much, but this approval was decidedly controversial.
我们不必深入太多 但这次批准明显的有争议性
The drug has failed to get approval in Europe due to the lack of evidence
这种药物在欧洲申请批准失败了 因为缺少
for its effectiveness, as well as some potential to cause swelling
证明疗效的证据 以及引起大脑肿胀
and bleeding in the brain.
流血的可能性
Understandably, some patients, families,
可以理解的 一些患者 家庭
and doctors are still willing to give aducanumab a shot.
及医生还是愿意试一试阿杜那单抗
Potential treatments for Alzheimer’s have so far been rare,
对阿尔茨海默病的潜在治疗目前为止已经十分稀有
and for some, the possibility of hope is better than nothing.
对一些人而言 有希望的机会总比什么都没有要好
For those who have relatives suffering from irreversible cognitive decline,
对于那些亲属遭受不可逆转的认知障碍
or face the prospect of it themselves in the near future,
或不久的将来自己可能面对这种疾病的人而言
using a drug that might work can seem like the obvious choice.
用一种可能起作用的药物似乎成了必然的选择
Among experts, there are mixed opinions — though a lot of them are pretty spicy.
在专家当中 有各种褒贬混杂的观点——然而它们中的大部分都十分激烈
Some people think it could invigorate research into Alzheimer’s,
一些人认为可以鼓励对阿尔茨海默病症的研究
whereas others think it could set it back decades.
但其他人认为可以让它推迟几十年
Like it or not, aducanumab is now heading toward what researchers
不管你喜不喜欢 阿杜那单抗现在正走向
are referring to as a phase four study:
研究人员称之为第四期的研究:
real world observation of effects on disease progression and cognition.
现实世界对疾病进展和认知的成效监测
We won’t know the outcome of this for several years.
几年内我们会不知道它的成效
And even if it fails this phase four trial, there’s a possibility that it might still
即使第四期试验未能通过
prove useful if given to younger people who are at risk
如果用在今后有风险患上阿尔茨海默病的年轻人身上
of developing Alzheimer’s later down the road.
仍有可能证明它还是有用的
See, there’s actually a lot of evidence that plaques alone
看 实际上有很多证据表明仅斑块
aren’t responsible for the kind of cognitive decline we see in this type of dementia.
不会造成我们在这类痴呆里看到的认知障碍
One of the main pieces of evidence we have for this is the fact that there are
我们所掌握的主要证据就是
plenty of people with amyloid plaques that show no signs of dementia at all.
许多有淀粉样蛋白斑块的人根本没有痴呆症状
In fact, some scientists have suggested that the prevalence of amyloid plaques
事实上 一些科学家已经认为 没患有阿尔茨海默病的人
could be just as high in those without Alzheimer’s as those with it.
含有的淀粉样蛋白斑块 可能与患此病者同样多
The amount of plaque also doesn’t correlate strongly with Alzheimer’s severity.
斑块数量也与阿尔茨海默症的严重程度没有密切的关系
However, there’s a difference in when different pathological features
然而 不同病理学特征
arise in the brain.
在大脑出现的时间有差异
Amyloid plaques appear first, about 10-20 years before cognitive symptoms start.
淀粉样蛋白最先出现 大概比认知症状开始要早10到20年
So clinical trials looking at the timing of starting therapy are already underway
因此 研究治疗开始时间的临床试验已经在进行中了
with different amyloid-clearing drugs.
其采用了不同清除淀粉样蛋白的药物进行实验
But it’s going to be a hot minute…
但那终将成为艰难时刻
or rather, a hot few decades, before we can take a look at results for studies like that.
或者说 艰难的数十年 在我们能看到一个像那样的研究成果之前
If aducanumab fails on all fronts at stopping cognitive decline,
若阿杜那单抗在阻止认知障碍的各方面上均失败了
it could be the final nail in the coffin of the Amyloid Hypothesis that dominated the field for many years.
这可能是多年来统治这个领域的淀粉样蛋白假说的终结
We tried every which way to clear plaques, and even succeeded.
我们尝试每一种途径消除斑块 甚至成功过
But if that doesn’t affect the clinical manifestation of the disease,
但倘若不能影响这种病的临床表现
that means we’re missing something about what causes it.
那意味着我们没发现真正的致病因
But, that doesn’t mean scientists are out of options.
但 这并不代表科学家们没有其他选项了
Right now, researchers are actively looking at a few other potential targets.
现在 研究人员正积极地考虑一些其他潜力目标
For starters, how about that other protein tangle I mentioned earlier: tau.
首先 例如我之前提到的另外一种蛋白质缠结tau
Treatments targeting tau also have a whole lot of potential.
针对tau的治疗 也有很多的可能性
In a healthy brain, tau is vital for maintaining the internal structure of neurons.
健康大脑中 tau对维持神经元的内部结构至关重要
But in Alzheimer’s, an abnormal form of tau builds up into tangles inside neurons,
但阿尔茨海默病者脑中 神经元内部会出现tau畸变体构建的缠结
and causes their internal skeleton structure to fall apart.
从而造成它们内框架结构的分崩离析
Those neurons then stop working as intended,
这些神经元就会停止原本工作
leading to a general decline in function of areas with a lot of tau build up.
导致许多tau堆积的区域功能普遍性下降
Now this probably isn’t going to be a case of pointing a finger at tau
现在这或许不会让人指着tau 而不是
instead of amyloid-beta and being all ‘ah ha, it was you all along!’.
β—淀粉样蛋白说 ‘阿哈 原来一直是你’
Clinical research is usually more complex than an Agatha Christie novel.
临床研究通常远比写一部阿加莎·克里斯蒂小说复杂得多
What actually seems to be going on is a complex relationship between tau,amyloid-beta,and other factors,
tau和β—淀粉样蛋白及其他因素间实际似乎正进行着复杂的联系
and that relationship evolves over the course of the disease.
那种联系在这种疾病范畴内演变
Tau starts out accumulating and replicating itself in areas related to memory,
Tau起初是在跟记忆相关的区域里积累和再生
namely the entorhinal cortex and hippocampus.
那些区域被称为内嗅皮质和海马体
And as amyloid continues to accumulate, things seem to reach a tipping point,
随着淀粉样蛋白持续积累 事情似乎达到一个顶点
which results in the abnormal tau starting to spread throughout the brain,
即造成畸变tau开始在整个大脑中蔓延
hopping from cell to cell.
在细胞之间快速移动
How exactly it does this, we’re not sure,
它具体怎么做的 我们不确定
but some evidence points to tau ‘seeds’ crossing synapses.
但有证据表明tau的‘种子’可能会穿过神经元突触
And as it spreads and grows and replicates,
随着它传播 生长 及再生
more and more neurons become damaged, driving cognitive decline.
越来越多的神经元被摧毁 导致认知衰退
Recent research has shown that in the mid-to-late stages of Alzheimer’s,
最新研究表明中晚期阿尔茨海默病者脑中
tau replication rather than spread seems to drive neurodegeneration onwards,
tau复制而不是tau蔓延 似乎才会迫使神经元退变持续
and therefore cognitive decline.
因此导致认知衰退
This gives one potential opening for a treatment.
这给了治疗一个潜在良机
What if we could design a drug that stopped tau replication, for example?
比如 假设我们能开发一种药物阻止tau复制呢?
Researchers are already exploring a lot of options,
研究人员已探索了许多选项
like therapies that stop tau from hopping from cell to cell,
比如 阻止tau在细胞之间快速移动
clear tau tangles, or stop tau from becoming abnormal in the first place.
清除tau缠结 或者在第一步阻止tau畸变的这些治疗方法
We have a lot of research on tau already, but the trouble is, much of that previous research
我们已有很多对tau的研究 但问题是 许多先前的研究
thought of tau as its own separate entity when it comes to Alzheimer’s.
涉及到阿尔茨海默病时 认为tau是它自己的独立体
But now, evidence is mounting that it has more of a synergistic relationship
但现在 更多的证据表明tau和β—淀粉样蛋白间
with amyloid-beta than being a lone ranger.
与其说是单独的作用体 倒不如说是协作关系
Not only does this give us a clue as to why amyloid-only approaches are falling flat,
这不仅提示我们为何只清除淀粉样蛋白质会一败涂地
but it may mean scientists have to reassess previous tau research
且或许意味着科学家也不得不透过这个方面重新审视
through this lens too.
先前tau的研究
It’s not just tau that scientists are homing in on, though.
然而科学家不只是把注意力集中于对tau的研究
Another popular avenue for research is the role inflammation might play.
另外一个受欢迎的研究途径就是炎症该表演的角色了
That is, we’re beginning to understand that the activity of the brain’s immune cells
即 我们开始了解大脑免疫细胞的活动
may be a third key feature of Alzheimer’s.
这许是阿尔茨海默病第三个关键特征
When pathogens or amyloid plaques build up,
当病原体或者淀粉样蛋白逐渐增加
these immune cells, called glial cells, try their best to clear them out.
这些被称为神经胶质细胞就会尽全力清除掉它们
In the process, they can set off inflammation in the brain.
在这个过程中 大脑就会引发炎症
When those glial cells go into overdrive in people with Alzheimer’s,
当阿尔茨海默病者脑中这些神经胶质细胞变得活跃
their inflammatory output seems to kill off neurons.
它们炎性输出似乎会杀死神经元
It also seems like this inflammation exacerbates both amyloid and tau build up.
炎症好像也会同时加剧淀粉样蛋白和tau的堆积
This lines up with what we’re seeing in genetic studies too.
这跟我们在遗传学研究中看到的相符
Large genetic studies have identified several genes that are related to
大量的遗传学研究已经识别到几种基因
an increased risk of developing Alzheimer’s,
这些基因不仅控制着大脑的免疫反应
as well as regulate the brain’s immune response.
而且 跟增加阿尔茨海默病风险也有关系
The jury’s still out on whether or not treating inflammation will be enough
评审团仍对治疗炎症是否就足够改善
to improve Alzheimer’s symptoms.
阿尔茨海默症状没有定论
So far, clinical trials of drugs designed to do that haven’t been successful.
目前为止 治疗炎症药物的临床实验药还没有成功过
But while we continue to figure out the cause of Alzheimer’s,
尽管我们在不断弄清阿尔茨海默病因
there are some slightly more futuristic treatment options on the horizon too.
但有一些稍稍更未来化的治疗也即将实现
As with a lot of conditions that have a genetic component,
如同许多有遗传学因素的条件一样
there’s already a lot of talk about the potential of gene therapies.
已经有大量关于基因疗法可能性的讨论
One example is a CRISPR-based approach, which is being trialed to target the genes
CRISPR基因编辑技术就是一例 它被测试靶向
that snip APP to weird lengths right there inside the brain,
大脑中把APP剪成奇怪长度的基因
though right now, it’s only been done in cell culture.
即使现在 它还只是在细胞培养中实现过
And an approach involving injecting restorative genes into the brain
一种涉及给大脑注射促进康复的基因法
was reported to have begun human clinical trials in 2021.
被报道已在2021年在人类临床试验上启用
These genes produce brain-derived neurotrophic factor, or BDNF, which is a
这些基因产生脑源性神经营养因子 或称为BDNF
protein that supports the survival and growth of new neurons and synapses.
这是一种支持新神经元和突触存活生长的蛋白质
In those with Alzheimer’s, levels of BDNF are diminished,
在阿尔茨海默患者脑中 BDNF指标降低
and researchers hope that increasing the amount of this protein will help keep symptoms at bay.
研究人员希望这种蛋白质数量的增加有助于抑制症状
While we await the outcome of aducanumab’s phase four trial,
在我们期待阿杜那单抗第四期试验结果时
there’s a lot more research still moving forwards.
更多的研究还在向前发展
If aducanumab fails, and fears based on previous data play out,
倘若阿杜那单抗失败 对先前数据的担忧就出现了
we are likely to see a lot of disappointment from patients and their families.
我们很可能看到患者及他们的家人无比失望
On a human level, that’s deeply understandable.
以人类角度看 是完全可理解的
From a purely scientific point of view, we want to update old hypotheses
以纯科学视角 我们理应以新数据
with new data, and discard them if they don’t fit the facts.
更新旧假说 如不符合事实就排除掉
And ethically speaking, we don’t want to give people something that doesn’t work,
道德上讲 我们不应该给人们一些无用的东西
or creates false hope.
或产生错误的希望
But being so close to what we once thought would be a cure,
但曾经被认为可能的治愈方法离我们如此之近
it can be hard to let that hope go.
想要放弃很难
Still, while it could fizzle into nothing, we’re far from out of options to pursue.
仍然 尽管它可能一败涂地 但我们还远不会没有研究的对象了
Because science never really ends, it just changes direction.
因为科学永远不会真正结束 只是需要改变方向
Thank you for watching this episode of SciShow.
感谢观看这一期的科学秀
I know that a lot of students and teachers welcome SciShow
我知道很多学生和老师都欢迎SciShow
into your classrooms and homes.
入驻你们的课堂及家里
So we’re proud to have today’s video sponsored by Linode, a cloud computing
所以很荣幸Linode对本期视频的赞助 它是
company that provides easy access to teaching tools like Moodle
一家云计算公司 可提供快捷获取像Moodle那样的
to make online learning and instructing more manageable.
教育工具 使线上学习和指导更易操作
On Moodle, you can make quizzes, collaborative projects,
在Moodle平台上 你可以做智力小游戏 合作项目
and checklists to help stay on track and keep classwork engaging.
以及有助进步和衔接课堂作业的清单
While grades aren’t quite as much fun,
然而评分等级并不那么有趣
it’s important to have a secure place to keep track of them.
重要的是有一个可靠的网址掌握最新消息
Linode knows how to keep online data secure and has earned the trust of Moodle users.
Linode能保证数据安全 已赢得Moodle用户信任
That’s over 200,000 students and educators around the world.
用户包括全世界超过20万人数的学生及教育者
So you can click the link in the description or head to linode.com/scishow
点击说明链接或登录linode·com/scishow
to check out Linode’s learning solutions.
即可查获Linode的学习答案
That link gives you a $100 60-day credit on a new Linode account.
链接赠送新账号一个价值100$ 60天的信用
Thanks to Linode for sponsoring this video.
再次感谢Linode对本期视频的赞助
[♪ OUTRO]
片尾曲

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视频概述

本视频主要介绍一种新型治疗阿尔茨海默病的药物,介绍它的工作原理以及被FAD批准的引起争议的原因,以及一些其他可能治疗阿尔茨海默病的途径

听录译者

收集自网络

翻译译者

丘陵

审核员

审核员SRY

视频来源

https://www.youtube.com/watch?v=c3iTqShlvBU

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