同行致遠(yuǎn) | 曾摘諾獎桂冠，如今劍指高血壓與肥胖——RNAi療法的進(jìn)擊之路 | Bilingual

編者按：2025年諾貝爾獎即將在下周揭曉。作為全球科學(xué)研究領(lǐng)域的至高榮譽(yù)之一，諾貝爾獎已走過一個多世紀(jì)，見證了無數(shù)推動人類文明進(jìn)步的偉大突破。從基礎(chǔ)科學(xué)的前沿探索到造福患者的臨床應(yīng)用，許多諾獎獲獎成果已成為現(xiàn)代醫(yī)學(xué)發(fā)展的基石，催生出改變疾病治療格局的創(chuàng)新療法。在這些成就中，RNA干擾（RNAi）機(jī)制的發(fā)現(xiàn)堪稱里程碑，不僅深化了我們對基因表達(dá)調(diào)控的理解，也直接催生了一類創(chuàng)新藥物——RNAi療法。如今，已有7款RNAi藥物獲批上市，為全球患者帶來切實(shí)的治療希望。作為全球創(chuàng)新的賦能者，藥明康德旗下獨(dú)特的CRDMO平臺WuXi TIDES，圍繞包括RNAi在內(nèi)的寡核苷酸藥物建立了一體化服務(wù)平臺，覆蓋從藥物發(fā)現(xiàn)、CMC開發(fā)，到商業(yè)化生產(chǎn)的全生命周期，加速將合作伙伴的創(chuàng)新構(gòu)想轉(zhuǎn)化為現(xiàn)實(shí)，造福全球病患。在今天的文章中，我們將回顧RNAi如何從實(shí)驗室走向臨床，從基礎(chǔ)研究轉(zhuǎn)化為惠及人類健康的現(xiàn)實(shí)成果，并展示W(wǎng)uXi TIDES賦能平臺如何幫助合作伙伴有效克服RNAi藥物開發(fā)中的多重挑戰(zhàn)。

意外而至的諾貝爾獎

2006年10月2日凌晨2點(diǎn)30分，斯坦福大學(xué)的Andrew Fire教授接到一通來電。電話那頭，一個略帶口音的聲音向他表示祝賀——諾貝爾獎委員會決定，由他與馬薩諸塞大學(xué)的Craig Mello教授共同分享當(dāng)年的諾貝爾生理學(xué)或醫(yī)學(xué)獎。

▲2006年諾貝爾生理學(xué)或醫(yī)學(xué)獎授予Andrew Fire和Craig Mello教授（圖片來源：NobelPrize.org）

和許多獲獎?wù)呦嗨疲現(xiàn)ire教授的第一反應(yīng)是“非常驚訝”，甚至一度懷疑對方撥錯了號碼。這種驚訝并非沒有原因：自上世紀(jì)80年代起，諾貝爾生理學(xué)或醫(yī)學(xué)獎得主的平均年齡多在60歲以上，但他當(dāng)年只有47歲，Mello教授更是只有45歲。而且，距離他們合作發(fā)表的關(guān)鍵論文問世，也只有短短8年的時間。這一切都來得太快，太不真實(shí)了。

許多生物學(xué)家指出，正是這些“不同尋常”的數(shù)字，印證了他們發(fā)現(xiàn)的非凡價值。“他們的發(fā)現(xiàn)是一個再明顯不過的諾貝爾獎，”諾獎得主Thomas Cech教授直言：“它在所有人的諾獎候選名單上。”幾乎沒有人質(zhì)疑他們的貢獻(xiàn)，這份榮譽(yù)實(shí)至名歸。

這項不同尋常的成果，正是RNA干擾機(jī)制的發(fā)現(xiàn)——一種通過雙鏈RNA實(shí)現(xiàn)基因沉默的機(jī)制。諾貝爾獎委員會稱，這是控制遺傳信息流的一個根本性機(jī)制，廣泛存在于植物、動物與人類體內(nèi)，并在生物技術(shù)與醫(yī)學(xué)領(lǐng)域擁有廣闊的應(yīng)用前景。

什么是RNAi？

有趣的是，這兩位科學(xué)家并非最早注意到RNAi現(xiàn)象的人。在他們之前，植物學(xué)家就已觀察到一系列難以解釋的現(xiàn)象。1990年，兩名研究者報道了一個令他們大感意外的發(fā)現(xiàn)：在矮牽牛花中，查爾酮合成酶（chalcone synthase）是一種在花青素合成通路里起到限速作用的酶。他們原以為提高這種酶的表達(dá)，就能加速花青素的合成，讓矮牽牛花的顏色變得更深。

但實(shí)驗結(jié)果與他們的預(yù)期截然相反。在引入表達(dá)查爾酮合成酶的基因后，矮牽牛花的顏色非但沒有變深，反而還變淺了！看著眼前的白色花朵，植物學(xué)家們感到無比困惑。后續(xù)的研究發(fā)現(xiàn)，經(jīng)過改造的矮牽牛花里頭，查爾酮合成酶的含量竟要比野生型低上50倍。這也讓研究人員們猜測，外源RNA的引入可能會使具有同源序列的基因“沉默”。

盡管這些植物學(xué)家做出了重要的觀察，并提出了潛在的作用機(jī)制，但他們卻一直沒有把這個發(fā)現(xiàn)轉(zhuǎn)化為實(shí)際應(yīng)用的技術(shù)。這也正是Fire教授與Mello教授的貢獻(xiàn)所在。在線蟲中，他們發(fā)現(xiàn)，只有注射與目標(biāo)基因序列一致或高度相近的雙鏈RNA，才能實(shí)現(xiàn)有效沉默。這原本可能是生物體的抗病毒機(jī)制，卻在演化的長河中被用作調(diào)控自身基因的手段。兩位科學(xué)家領(lǐng)導(dǎo)的工作，使研究者得以用更簡便的方法精準(zhǔn)調(diào)控基因，為生命科學(xué)研究開辟新路徑。

可以說，這項突破性的技術(shù)，打開了一扇通往新天地的大門。這一創(chuàng)新工具得到了許多生物實(shí)驗室的青睞，也加速了生物學(xué)的發(fā)展。更重要的是，它讓我們看到了通過“基因沉默”治療疾病的希望。正如諾貝爾獎官方新聞稿中所言，“RNA干擾已經(jīng)在基礎(chǔ)科研中廣泛應(yīng)用，用于研究基因功能，并有望在未來帶來全新的療法。”

“我相信這一技術(shù)將在未來10年里，在抗癌領(lǐng)域得到廣泛應(yīng)用。”時任冷泉港實(shí)驗室主席，美國科學(xué)院院士Bruce Stillman博士說道。

熱情與現(xiàn)實(shí)

人們的樂觀并不是沒有理由：在諾貝爾獎頒發(fā)的5年前，人類基因的測序工作已經(jīng)完成。許多研究人員早就開始在哺乳動物細(xì)胞里嘗試應(yīng)用RNAi，生物技術(shù)公司如雨后春筍般涌現(xiàn)，爭當(dāng)?shù)谝豢頡NAi新藥的發(fā)明人。

這一熱潮背后有清晰的邏輯：許多疾病源于致病蛋白的出現(xiàn)，而傳統(tǒng)小分子藥物的作用機(jī)理，正是結(jié)合這些蛋白，抑制其功能。使用RNAi技術(shù)則有望從源頭抑制蛋白表達(dá)，將這些致病蛋白扼殺在萌芽之中。由于雙鏈RNA易于合成，若能成功，既可避免漫長的化合物篩選，也可能攻克“不可成藥”靶點(diǎn)帶來的難題。因此，產(chǎn)業(yè)界對RNAi療法有著極為高漲的研發(fā)熱情，一些大型藥企亦相繼入局。

然而，熱潮之下，問題逐漸浮現(xiàn)出來。其中，研究人員們無法解決的一大難題，在于如何在特定細(xì)胞內(nèi)精準(zhǔn)啟動RNAi。更糟糕的是，部分項目在僅有初步實(shí)驗依據(jù)時便匆忙進(jìn)入人體試驗。

“早期許多臨床試驗并不明智，很多人只是為了搶第一，”斯坦福大學(xué)的基因療法專家Mark Kay教授說道：“大部分保持理性且深諳這一領(lǐng)域的人都知道，這些試驗難以成功。”

不久之后，這些隱患逐漸顯現(xiàn)，一些RNAi療法在人體中暴露出意料之外卻在情理之中的嚴(yán)重副作用。由于無法遞送到人體內(nèi)的正確細(xì)胞，這些療法要么沒有效果，要么反而對人體有害。

整個RNAi領(lǐng)域迅速降溫，諸多生物醫(yī)藥公司選擇退出。2014年，一家名為Sirna Therapeutics的RNAi技術(shù)公司被折價出售。而購買它的，則是一家名為Alnylam Pharmaceuticals的生物技術(shù)公司。

最亮的星

Alnylam成立于2002年，恰處于RNAi從科學(xué)突破（1998年）到斬獲諾獎（2006）的中點(diǎn)。它的名字源于“Alnilam”，中文名是“參宿二”，指的是夜空中距離我們2000光年外的獵戶座腰帶中點(diǎn)。

如同漫天群星一般，在10多年前，到處都能看到研發(fā)RNAi技術(shù)的新銳公司，Alnylam看起來并不起眼；但在RNAi療法跌入低谷時，Alnylam卻是少數(shù)堅持者之一。這并不代表它未曾經(jīng)歷過陣痛。在Alnylam公司官網(wǎng)上寫道，其成立早期也曾遇到過許多挑戰(zhàn)：合作伙伴的離去、外界對于技術(shù)的喪失信心，都給Alnylam帶來了不小的打擊。只有在公司內(nèi)部，才能看到將RNAi療法變成現(xiàn)實(shí)的信念與樂觀。

▲這篇論文改變了RNAi療法的進(jìn)程

當(dāng)然，無數(shù)案例證明，僅憑信念與樂觀是不夠的。真正推動Alnylam前進(jìn)的，是其在RNAi療法“至暗時刻”取得的關(guān)鍵技術(shù)突破。2010年，這家公司發(fā)表了一篇足以影響整個RNAi療法領(lǐng)域的論文。這項研究不但闡述了脂質(zhì)納米顆粒（LNP）靶向遞送RNAi藥物的機(jī)制，還介紹了基于N-乙酰半乳糖胺（GalNAc）偶聯(lián)的靶向遞送策略。利用LNP和GalNAc偶聯(lián)技術(shù)，人們終于能對RNAi療法進(jìn)行肝臟靶向遞送。橫亙在科學(xué)家們前進(jìn)道路上的最大阻礙自此被移除，通往首款RNAi療法的道路逐漸清晰。

首款RNAi療法

找到解決問題的關(guān)鍵后，Alnylam迅速建立起一系列研發(fā)管線，聚焦多種罕見的遺傳疾病。其中，領(lǐng)先項目patisiran用于治療的是一種叫做遺傳性轉(zhuǎn)甲狀腺素蛋白介導(dǎo)（hATTR）淀粉樣變性的疾病。這種疾病的根源在于編碼轉(zhuǎn)甲狀腺素蛋白的基因發(fā)生突變，導(dǎo)致淀粉樣蛋白在人體內(nèi)的異常積累，對器官和組織造成損傷。這是一種嚴(yán)重而致命的罕見病，患者從癥狀發(fā)作起，預(yù)期壽命只有2-15年。

而patisiran則能發(fā)揮RNAi對基因的“沉默”效果。通過抑制特定mRNA的表達(dá)，這款療法能有效阻止變異轉(zhuǎn)甲狀腺素蛋白的生成，清除組織里的淀粉樣蛋白沉積，恢復(fù)組織功能。

2017年9月，Alnylam與其合作伙伴賽諾菲（Sanofi）公布了patisiran在3期臨床試驗中的積極頂線結(jié)果。研究表明，這款新藥達(dá)到了主要臨床終點(diǎn)以及所有次要臨床終點(diǎn)。在18個月時，與安慰劑相比，patisiran顯著減少了患者的神經(jīng)病變，提高了他們的生活質(zhì)量。

2個月后，Alnylam啟動了滾動遞交上市申請，以加速上市進(jìn)程。美國FDA也授予patisiran突破性療法認(rèn)定和孤兒藥資格。8月3日，英國授予patisiran“早期獲取”（Early Access）資格，允許患者在這款療法正式問世前，就能得到治療。在2018年，人類終于迎來了首款RNAi療法的獲批。

GalNAc偶聯(lián)技術(shù)催生多款獲批療法

首款RNAi療法獲批之后，GalNAc偶聯(lián)技術(shù)因其卓越的肝臟靶向性、高效的細(xì)胞攝取率和良好的安全性特征，成為肝臟靶向寡核苷酸療法開發(fā)的首選遞送策略。迄今為止獲批的7款RNAi療法中，6款使用GalNAc偶聯(lián)技術(shù)完成肝臟特異性遞送。

自問世以來，GalNAc偶聯(lián)技術(shù)不斷迭代升級，無論是在化學(xué)修飾方式還是多價分子的設(shè)計合成方面，均取得顯著進(jìn)展。由于去唾液酸糖蛋白受體（ASGPR）對GalNAc的親和力與其配體數(shù)目密切相關(guān)，研究人員廣泛探索并開發(fā)了多種三價、四價GalNAc簇（cluster）及其在寡核苷酸上的偶聯(lián)策略，以提高遞送效率。

隨著技術(shù)不斷成熟，GalNAc偶聯(lián)藥物的合成與工藝開發(fā)日益復(fù)雜。WuXi TIDES團(tuán)隊在合成GalNAc分子方面擁有豐富經(jīng)驗，已合成100多種GalNAc分子及其衍生物，包括單-GalNAc、三-GalNAc、四-GalNAc、GalNAc酰胺、GalNAc PFP酯、GalNAc N3和GalNAc-PEG偶聯(lián)物等。借助全面的平臺能力，WuXi TIDES能夠提供GalNAc定制合成、工藝開發(fā)和生產(chǎn)一體化服務(wù)，支持從藥物發(fā)現(xiàn)到臨床開發(fā)再到商業(yè)化生產(chǎn)。下面的案例將介紹WuXi TIDES如何幫助合作伙伴加速推進(jìn)GalNAc偶聯(lián)siRNA藥物的開發(fā)。

14個月完成兩款GalNAc偶聯(lián)siRNA藥物IND申報準(zhǔn)備

一家生物技術(shù)公司在開發(fā)用于治療心血管疾病的GalNAc偶聯(lián)siRNA候選藥物時，由于缺乏成熟的GalNAc分子來源，加上產(chǎn)率和粗純度低下等問題，項目推進(jìn)受阻。他們找到了WuXi TIDES，尋求解決方案。

首先要解決的便是非常規(guī)GalNAc分子的供應(yīng)問題。針對合作伙伴提出的特殊需求，團(tuán)隊迅速建立合成路線，采用先進(jìn)的流動化學(xué)技術(shù)，并優(yōu)化了溶劑體系，使重結(jié)晶收率高達(dá)94.8%，4個月內(nèi)成功交付4.5公斤高純度定制GalNAc分子，有效保障了項目的原料供應(yīng)。

隨后，在關(guān)鍵的偶聯(lián)環(huán)節(jié)，憑借在多種偶聯(lián)類型、偶聯(lián)化學(xué)和修飾策略上的積累，WuXi TIDES團(tuán)隊選擇了具有高度選擇性的“點(diǎn)擊化學(xué)”策略，顯著降低副產(chǎn)物產(chǎn)生，簡化合成和純化流程，使最終收率從13%提升至62%，粗品純度從18%提高到75%，確保了適合臨床試驗的高純度和穩(wěn)定性。

同時，基于一體化CMC服務(wù)能力，WuXi TIDES團(tuán)隊平行開展了分析方法、制劑開發(fā)等多項工作，同時利用先進(jìn)的無菌灌裝生產(chǎn)線和優(yōu)化的生產(chǎn)流程設(shè)計，在GMP批次的生產(chǎn)中達(dá)到99%的產(chǎn)率，顯著降低了API的損失。多團(tuán)隊的全方位協(xié)作使兩款siRNA候選藥物在14個月內(nèi)順利完成了IND申報準(zhǔn)備，加速推進(jìn)至臨床階段。

以上案例只是WuXi TIDES一體化CRDMO平臺能力的一個縮影。除了GalNAc偶聯(lián)寡核苷酸，WuXi TIDES也可為GalNAc偶聯(lián)多肽藥物提供一站式開發(fā)支持。隨著越來越多GalNAc偶聯(lián)藥物進(jìn)入臨床開發(fā)階段，像這樣的產(chǎn)業(yè)協(xié)同將成為加快研發(fā)步伐的重要推動力。

展望未來

在首款RNAi療法獲批之后的7年中，又有6款RNAi療法獲批上市，治療的疾病類型也從罕見病擴(kuò)展到患者人數(shù)眾多的常見病，有望變革高血壓、高血脂和肥胖癥等慢性病的治療模式。據(jù)統(tǒng)計，截至今年7月，全球在研RNAi療法接近400款，其中約三分之一已進(jìn)入臨床開發(fā)階段。RNAi領(lǐng)域的“明星公司”Alnylam表示，預(yù)計在2030年前解決主要組織的遞送挑戰(zhàn)，最大限度地釋放RNAi技術(shù)的潛力。面向未來，WuXi TIDES將持續(xù)基于其一體化CRDMO平臺，賦能包括RNAi在內(nèi)的寡核苷酸藥物開發(fā)，助力合作伙伴加快將科學(xué)創(chuàng)新轉(zhuǎn)化為新藥、好藥，造福全球病患。

Two Decades On: How RNAi Evolved from Nobel Discovery to New Medicines

The 2025 Nobel Prizes will be announced next week. As one of the top honors in global scientific research, the Nobel Prize has, for more than a century, recognized discoveries that have propelled human civilization forward. From frontier explorations in basic science to clinical applications that improve lives, Nobel-winning breakthroughs have laid the foundation of modern medicine and inspired therapies that transform how we treat disease. Among these achievements, the discovery of RNA interference (RNAi) stands as a milestone. It not only deepened our understanding of gene regulation but also directly led to the creation of a new class of medicines—RNAi therapies. Today, seven RNAi therapies have been approved worldwide, offering real treatment hope for patients.

WuXi TIDES, an integral part of WuXi AppTec, has established a CRDMO platform for RNAi and other oligonucleotide therapies. The platform provides high-throughput library synthesis and custom synthesis, covering all types of oligonucleotides, their monomers, linkers, ligands and conjugates. It supports all stages of development, from drug discovery and CMC development to commercial-scale manufacturing, accelerating the translation of innovative ideas into clinical reality for partners worldwide. In this article, we trace RNAi’s journey from the laboratory to the clinic and highlight how the WuXi TIDES platform helps overcome the critical challenges of RNAi drug development.

A Nobel Prize Arrives Unexpectedly

At 2:30 a.m. on October 2, 2006, Stanford University professor Andrew Fire received a call. On the line was a voice with a slight accent offering congratulations: the Nobel Committee had decided that he and Dr. Craig Mello of the University of Massachusetts would share that year’s Nobel Prize in Physiology or Medicine.

Like many laureates, Fire’s first reaction was disbelief—he even wondered whether the caller had dialed the wrong number. His surprise was understandable. Since the 1980s, Nobel laureates in Physiology or Medicine had typically been in their 60s or older. Fire was only 47, and Mello just 45. What’s more, their landmark paper had been published only eight years earlier. It all seemed too sudden, almost unreal.

Scientists quickly pointed out that these unusual numbers only underscored the significance of their discovery. “Their discovery is as obvious a Nobel as you can get,” remarked Nobel laureate Dr. Thomas Cech, “It was on everyone’s shortlist.” Few questioned the importance of their work. The honor was widely regarded as inevitable.

That work was the discovery of RNA interference, a mechanism by which double-stranded RNA silences gene expression. The Nobel Committee described it as a fundamental biological process for controlling genetic information, present in plants, animals, and humans, with vast potential in biotechnology and medicine.

What Is RNAi?

Fire and Mello were not the first to observe RNAi-like effects. In the early 1990s, plant scientists noticed puzzling phenomena. In 1990, researchers working on petunias hypothesized that overexpressing chalcone synthase, an enzyme in anthocyanin biosynthesis, would deepen flower color. Instead, the modified plants became lighter. Later studies showed that chalcone synthase levels in the altered petunias were up to 50 times lower than in wild-type plants, suggesting that the introduced RNA had “silenced” homologous genes.

Although these researchers proposed possible mechanisms, they did not develop a practical technology. Fire and Mello did. In

C. elegans

The implications were enormous. RNAi quickly became a staple in laboratories, accelerating biological research. More importantly, it opened the door to treating diseases through “gene silencing.” As the Nobel press release noted, “RNA interference is already widely used in basic research to study gene function and may lead to novel therapies in the future.” Dr. Bruce Stillman, then president of Cold Spring Harbor Laboratory, predicted, “This technology will find broad application in the next 10 years in the fight against cancer.”

Enthusiasm and Reality

The optimism had a strong foundation. The human DNA had been sequenced, and biotech startups rushed to harness RNAi, hoping to deliver the first therapeutic. The rationale was compelling: many diseases are caused by pathogenic proteins, and while small molecules act by inhibiting proteins, RNAi promised to silence them at the source. Because double-stranded RNA is easy to synthesize, RNAi offered a faster route to therapy and a way around “undruggable” targets. The field attracted intense industry interest, including from large pharmaceutical companies.

But enthusiasm soon collided with reality. A central challenge was how to trigger RNAi precisely in the right cells. Despite limited preclinical validation, some programs advanced hastily into human trials. "Many early trials were unwise. People just wanted to be first," recalled Stanford gene therapy expert Dr. Mark Kay, "Those who stayed rational knew they wouldn’t succeed."

It didn’t take long for problems to surface. Some RNAi therapies proved ineffective, or even harmful, because they couldn’t reach the intended cells. The field cooled quickly, and many companies exited. In 2014, an RNAi company called Sirna Therapeutics was sold at a discount. The buyer was a small biotech: Alnylam Pharmaceuticals.

The Brightest Star

Founded in 2002, midway between the 1998 breakthrough and the 2006 Nobel Prize, Alnylam took its name from “Alnilam”, the central star in Orion’s Belt. A decade ago, amid a crowded field of RNAi startups, Alnylam did not stand out. But when the field hit its low point, it endured while many others disappeared.

Alnylam’s survival was not without difficulty. As the company has recalled, it faced partner withdrawals and waning external confidence in RNAi. What sustained it was internal conviction that RNAi medicines could be made a reality.

What ultimately propelled Alnylam forward was a critical technical advance. In 2010, the company published a landmark paper describing how lipid nanoparticles (LNPs) could deliver RNAi therapies, and how N-acetylgalactosamine (GalNAc) conjugation could achieve precise liver targeting. With these innovations, the biggest obstacle, effective delivery, was finally overcome. The path to the first RNAi therapy became clear.

The First RNAi Therapy

With the delivery problem solved, Alnylam built a pipeline focused on rare genetic diseases. Its lead program, patisiran, targeted hereditary transthyretin-mediated (hATTR) amyloidosis, a fatal disorder caused by transthyretin mutations that lead to amyloid buildup in tissues. Patients typically survive only 2–15 years after symptom onset.

Patisiran silences the mutant gene, preventing production of faulty transthyretin protein, clearing amyloid deposits, and restoring function. In September 2017, Alnylam and Sanofi reported positive Phase 3 results: patisiran met all endpoints, significantly reduced neuropathy, and improved quality of life over 18 months compared with placebo.

Two months later, Alnylam began a rolling submission to accelerate approval. The FDA granted Breakthrough Therapy and Orphan Drug designations. In 2018, the world welcomed the first approved RNAi therapy.

GalNAc Conjugation Enables Multiple Approvals

Since then, GalNAc conjugation has become the gold standard for liver-targeted oligonucleotide delivery, offering high uptake and good safety. Of the seven approved RNAi therapies, six use GalNAc conjugation.

Since its introduction, GalNAc conjugation has evolved significantly through advances in chemical modification and the development of multivalent GalNAc clusters. Research shows that asialoglycoprotein receptor (ASGPR) binding affinity improves with the number of GalNAc ligands present, prompting the development of tri- and tetra-valent GalNAc constructs and optimized strategies for their conjugation to oligonucleotides.

As the technology matures, the synthesis and process development of GalNAc-conjugated drugs have grown increasingly complex. WuXi TIDES brings extensive experience in this area, having synthesized more than 100 types of GalNAc molecules and derivatives—including mono-GalNAc, tri-GalNAc, tetra-GalNAc, GalNAc amidites, GalNAc PFP esters, GalNAc N3, and GalNAc-PEG conjugates. Through the company’s comprehensive capabilities and capacity, WuXi TIDES offers GalNAc custom synthesis, process development, and manufacturing support from the discovery phase to commercial launch. The following case study illustrates how WuXi TIDES helped a biotech partner rapidly advance a GalNAc-siRNA candidate.

Fast-Track to Phase 1: Two siRNA IND CMC Packages Completed in 14 Months

One biotech company developing a GalNAc-siRNA therapy for cardiovascular disease faced multiple challenges—including limited supply of a unique GalNAc molecule, low yield, and poor purity—which stalled their program. To overcome these hurdles, they partnered with WuXi TIDES.

The priority was to ensure a stable supply of the GalNAc molecule. WuXi TIDES quickly designed a customized synthetic route tailored to the client’s specifications. Using advanced flow chemistry and an optimized solvent system, the team achieved a 94.8% recrystallization yield. Within just four months, they successfully delivered 4.5 kilograms of high-purity, custom GalNAc—effectively securing the supply of the starting material for the GalNAc-siRNA conjugate and shortening development timelines.

Next came the critical conjugation step. Drawing on extensive expertise in conjugation chemistries and modification strategies, the WuXi TIDES team adopted a highly selective “Click Chemistry” approach, minimizing byproduct formation and simplifying synthesis and purification. As a result, the overall yield increased from 13% to 62%, and crude purity improved from 18% to 75%, ensuring the production of clinical-grade material with superior purity and stability.

In parallel, WuXi TIDES leveraged its integrated CMC capabilities to advance analytical method development and formulation optimization. Together with an advanced sterile fill-finish line and optimal process design, we achieved a batch yield of >99% in GMP production, significantly minimizing the overall loss of costly API. These coordinated efforts enabled two siRNA candidates to complete IND-enabling activities within just 14 months, accelerating progress toward the clinic.

This case is just one example of the capabilities of WuXi TIDES’ integrated CRDMO platform. In addition to oligonucleotides, WuXi TIDES also provides comprehensive development solutions for GalNAc-conjugated peptide therapeutics. As more GalNAc-conjugated drugs advance into clinical development, integrated collaboration will be essential to accelerating innovation and bringing therapies to patients faster.

Looking Ahead

As of July this year, nearly 400 RNAi candidates are in development globally, with about one-third already in clinical stages. Alnylam, a recognized leader, has stated its goal of solving delivery challenges across major tissues by 2030 to unlock the full potential of RNAi.

Looking forward, WuXi AppTec will continue to leverage its integrated, end-to-end CRDMO platform to support partners in accelerating the transformation of scientific innovation into impactful medicines that improve lives worldwide.

參考資料：

[1] 2 American ‘Worm People’ Win Nobel for RNA Work. Retrieved, September 5, 2025, from https://www.nytimes.com/2006/10/03/science/03nobel.html

[2] Andrew Fire shares Nobel Prize for discovering how RNA can switch off genes. Retrieved September 5, 2025, from https://news.stanford.edu/news/2006/october4/nobel-100206.html

[3] When a Nobel Prize brings a shower of hype: the roller coaster ride of RNAi. Retrieved September 5, 2025, from https://www.statnews.com/2016/09/29/nobel-prize-rnai-biotech/

[4] Average Age for for Nobel Laureates in Physiology or Medicine. Retrieved September 5, 2025, from https://www.nobelprize.org/nobel_prizes/lists/laureates_ages/medicine_ages.html

[5] Sen and Blau (2006). A brief history of RNAi: the silence of the genes. The FASEB Journal. https://doi.org/10.1096/fj.06-6014rev

[6] Suhr et al., (2015). Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet Journal of Rare Diseases. https://doi.org/10.1186/s13023-015-0326-6

[7] Akinc et al., (2010). Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Molecular Therapy. https://doi.org/10.1038/mt.2010.85

[8] Alnylam and Sanofi Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR (hATTR) Amyloidosis Patients with Polyneuropathy. Retrieved September 5, 2025, from http://investors.alnylam.com/news-releases/news-release-details/alnylam-and-sanofi-report-positive-topline-results-apollo-phase

[9] "Press Release: The 2006 Nobel Prize in Physiology or Medicine". Nobelprize.org. Nobel Media AB 2014. Retrieved September 5, 2025, from http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/press.html

[10] Cui et al., (2021). Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation. ACS Omega, DOI:10.1021/acsomega.1c01755.

[11] Gene, Cell, & RNA Therapy Landscape Report. Q2 2025 Quarterly Data Report. Retrieved September 5, 2025, from https://www.asgct.org/global/documents/cl-080125report-asgct-citeline-q2-2025-jn7765-fina.aspx

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