Recently The New York Times reported the following:
A Disease That Makes Children Age Rapidly Gets Closer to
a Cure (2/2)
The New York Times - By Gina Kolata
July 24, 2024, 5:00 a.m. ET
(continue)
The Easy Part
Dr. Collins began by giving a new postdoctoral fellow in his
lab an assignment: Find the cause of progeria.
“Let’s give it a year,” he told her.
That turned out to be the easy part. It took Maria Eriksson, the fellow, just a few months. A single letter among the string of three billion individual letters — each either a G, A, C and T — that make up human DNA was changed. In a particular spot in a gene known as lamin A, one of those letters is substituted for another. The result is the production of a toxic protein, progerin, which disrupts the scaffolding that keeps the nucleus of a cell in its proper shape.
Dr. Eriksson, Dr. Collins and colleagues published a paper explaining the finding in 2003.
The mutation in lamin A occurs in a sperm or egg cell before fertilization. It is simply a random bit of terrible luck.
With the aberrant progerin, cells start to deteriorate after a few divisions, looking more and more unusual. Eventually, the deterioration sets off a signal in the cells to self-destruct.
The next step in the research was to put the lamin A mutation into mice. As in humans with the disease, the animals aged quickly, developed heart disease, had wrinkled skin and lost their hair. And they died young.
But it wasn’t until the emergence of CRISPR, a DNA-cutting technology, in 2012 that the small research group thought a bold new treatment could be devised. CRISPR can slice DNA and disable a gene. That, though, was far from ideal — what was really needed was something that could repair a gene.
The solution arose in 2017 from the lab of David Liu, a Harvard professor who is director of the Merkin Institute for Transformative Technologies in Healthcare. His group invented a gene editing system that acts like a pencil at the site of a mutation, using an enzyme to erase one of the DNA letters — adenine, or A — and write in a guanine, or G. That is exactly what is needed to correct the progeria mutation.
That gene editing enzyme is never seen in nature. Nicole Gaudelli, who was a postdoctoral researcher in Dr. Liu’s lab at the time, produced one anyway with a survival-of-the-fittest experiment: Dr. Gaudelli forced bacteria to either make the enzyme or die. (Dr. Liu is a co-founder of several gene editing companies aimed at treating more common diseases.)
Dr. Liu called the system invented by his group “base editing” because it directly edits the letters, or the bases, that make up DNA.
In one test, Luke Koblan, a graduate student working in Dr. Liu’s laboratory, tried to fix the progeria mutation in patients’ cells growing in petri dishes. His experiment succeeded.
Dr. Liu was thrilled. He’d watched documentaries on progeria, and the patients had touched his heart.
In 2018, Dr. Liu was invited to give a seminar at the N.I.H. He knew Dr. Collins would be in the audience, so he added a few slides on base editing cells from progeria patients.
Dr. Collins was riveted. He called Dr. Gordon to tell her what he’d heard.
“It was like a lightning bolt,” Dr. Gordon said.
Here, at last, was real hope.
“I’m like, ‘Oh my gosh, let’s go,’” Dr. Collins recalled.
The Hard Part
The results, documented in a 2021 paper, far exceeded their cautious hopes. Almost all of the damage to large heart arteries, a hallmark of the disease, was reversed. The mice looked healthy. They kept their hair. And they lived to the start of old age in mice — around 510 days — instead of dying at 215 days with progeria.
To streamline manufacturing and minimize potential side effects of the delivery method, Dr. Liu’s group had to shrink the size of the gene editor, which was too large to be delivered to cells in a single molecular carrier. That was a tall order because even the original DNA-cutting CRISPR scissors system from nature does not fit into a single such delivery mechanism.
Once they achieved the shrinking, the researchers had to test the new gene editing enzyme in mice and see if the editing was still working. It was.
Now, they are running a longer experiment to see if the mice live to old age.
While they wait, the researchers are figuring out the next steps to use their innovations to cure children with progeria. The team meets on Zoom every Monday at 4 p.m.
Their goal is to obtain permission from the Food and Drug Administration to start a clinical trial.
A key step will be finding a manufacturing partner to make the base editor for use in humans.
“We want to start this trial in two years or less,” Dr. Collins said.
And if it works? If progeria base editing helps show the way for the thousands of other genetic diseases with no treatment?
Translation
（繼續）
容易的部分
Collins 博士首先給他實驗室的一位新博士後研究一項任務：找出早衰症的原因。
他告訴她:「讓我們給這任務一年時間吧」。
事實證明這是最簡單的部分。Maria Eriksson 這個博士後研究員只花了幾個月的時間。構成人類 DNA 的 30 億個單獨字母（每個字母都是 G、A、C 和 T）中的一個字母被改變了。在稱為核纖層蛋白 A 的基因的特定位置中，其中一個字母被另一個字母取代。結果是產生一種有毒蛋白質 - 早老素，它會破壞使細胞核保持適當形狀的支撑架。
Eriksson 博士、Collins 博士及其同事於 2003 年發表了一篇論文解釋了這項發現。
核纖層蛋白 A 的突變發生在受精前的精子或卵細胞。這只是一個隨機的可怕的運氣。
由於早老素異常，細胞在幾次分裂後開始退化，看起來越來越不尋常。最終，這種退化會在細胞中引發自毀訊號。
研究的下一步是將核纖層蛋白 A 突變放入小鼠體內。與患有這種疾病的人類一樣，這些動物衰老得很快，患有心臟病，皮膚出現皺紋，毛髮脫落。它們很早就死亡。
但直到 2012 年 DNA 切割技術 CRISPR 出現，這個小研究團隊才認為可以設計出大膽的新療法。 CRISPR 可以切割 DNA 並停用某一個基因。然而，這遠非理想 - 真正需要的是一種能夠修復基因的東西。
此解決方案於 2017 年由哈佛大學教授、Merkin 醫療保健變革技術研究所所長 David Liu 的實驗室提出。他的團隊發明了一種基因編輯系統，該系統在突變位點的作用就像一支鉛筆，使用一種酶擦除DNA 字母之一 - 腺嘌呤（即A）- 並寫入鳥嘌呤（即 G）。這正是矯正早衰突變所需要的。
這種基因編輯酶在自然界中從未見過。當時 Nicole Gaudelli 是 Liu 博士實驗室的博士後研究員，無論如何，他通過一種適者生存的實驗生產出了一種酶：Gaudelli 博士強迫細菌要么製造這種酶，要么死亡。 （Liu 博士是多家旨在治療更常見疾病的基因編輯公司的共同創辦人）
Liu 博士將他的團隊發明的系統稱為 “鹼基編輯” ，因為它直接編輯 DNA 的字母或鹼基。
在一項測試中，在Liu博士實驗室工作的研究生 Luke Koblan 試圖修復培養皿中生長的患者細胞中的早衰突變。他的實驗成功了。
Liu 博士激動不已。他看過有關早衰症的紀錄片，病人的經歷觸動了他的心。
2018年，Liu 博士受邀在N.I.H.做研討會。他知道 Collins 博士會在觀眾席中，因此他添加了幾張關於早衰症患者的鹼基編輯細胞的幻燈片。
Collins 博士全神貫注。他打電話給 Gordon 醫生，告訴她他所聽到的情況。
Gordon 醫生說: 「這就像一道閃電」。
終於，真正的希望出現了。
Collins 博士回憶道: 「我當時想，『天哪，我們去開展工作吧』」。
困難的部分
美國衛生研究院的研究人員首先尋求改善早衰小鼠的健康狀況。他們首先嘗試性地單次注入鹼基編輯器。
結果記錄在2021 年的一篇論文中,它遠遠超出了他們謹慎的希望。幾乎所有對大心臟動脈的損傷（該疾病的標誌）都得到了逆轉。老鼠看起來很健康。他們保留了頭髮。它們活到了老鼠中的老年期 - 大約 510 天 - 而不是因早衰症而死亡的 215 天。
為了簡化製造並最大程度地減少傳遞方法的潛在副作用，Liu 博士的團隊必須縮小基因編輯器的尺寸，因為基因編輯器太大而無法透過單一分子載體傳遞到細胞。這是一項艱鉅的任務，因為即使是來自大自然的原始 DNA 切割 CRISPR 剪刀系統也不適合單一的此類傳遞機制。
一旦縮小編輯器，研究人員就必須在小鼠身上測試新的基因編輯酶，看看編輯是否仍然有效。結果是它是仍然有效。
現在，他們正在進行一項時間更長的實驗，看看老鼠是否能活到老年。
在等待的同時，研究人員正在製定下一步計劃去利用他們的創新來治療早衰症兒童。該團隊每週一下午 4 點在 Zoom 上開會。
他們的目標是獲得美國食品和藥物管理局的許可來啟動臨床試驗。
關鍵一步是尋找製造合作夥伴來製造用於人類的鹼基編輯器。
Collins 博士說: 「我們希望在兩年或更短的時間內開始這項試驗」。
如果有效的話？早衰症鹼基編輯是否有助於為數以千計的其他無法治療的遺傳疾病指明道路？
Collins 博士說: 「之後, 哇」。
So, a cure for an ultrarare disease, progeria,
could be on the horizon. Now, a small group of academics and government
scientists are working on an innovative gene editing technique. This is an
inspiring story on how American scientists, out of curiosity and passion, set
out to do something good for human kind by helping the infortune. They do it
for the benefit of humanity rather than for money. Life is always full of hope
in this kind of society where individuals can live out their lives base on
their own free will. If their research is a success, it will mean that many
more types of similar genetic discases can be cured. This will be good news for
everyone.
Note:
1. There are four nucleotides, or bases, in DNA: adenine (A),
cytosine (C), guanine (G), and thymine (T). These bases form specific pairs (A
with T, and G with C). Molecules called nucleotides, on opposite strands of the DNA double
helix, that form chemical bonds with one another are called base pair. These
chemical bonds act like rungs in a ladder and help hold the two strands of DNA
together. (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/base-pair)
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