Nedosiran

2025 年 6 月 9 日，随着多家药企在 RNA 干扰（RNAi）领域的持续突破，小干扰 RNA（siRNA）疗法正站在关键转折点。继 Alnylam 在肝脏靶向治疗中取得显著成功后，行业正全力攻克多器官递送难题，一场从 "肝脏专属" 到 "全身布局" 的技术革命已然拉开序幕。一、肝脏靶向的辉煌：Alnylam 奠定行业基石2025 年 3 月，Alnylam 再获两项 FDA 批准：Amvuttra 用于转甲状腺素蛋白介导的淀粉样变性，与赛诺菲合作的 Qfitlia 则针对血友病 A 和 B。这一成就延续了该公司的创新轨迹 ——2018 年，其首款 siRNA 药物 Onpattro 获批，标志着 RNAi 疗法从实验室走向临床的重大突破。回顾技术演进，1998 年 Craig Mello 发现 RNA 干扰机制，2002 年 Alnylam 成立，直至 2014 年 GalNAc 配体技术问世，才真正解决了 siRNA 的肝脏靶向难题。Onpattro 通过 GalNAc 偶联技术，首次实现了在肝脏细胞中特异性沉默致病基因，不仅缓解遗传性转甲状腺素蛋白淀粉样变性多发性神经病的症状，更实现了功能改善，被行业分析师 Myles Minter 称为 "革命性突破"。目前，Alnylam 已有多款药物获批，涵盖高胆固醇血症（与诺华合作的 Leqvio）、急性肝卟啉症（Givlaari）等领域。诺和诺德的 Rivfloza 也于 2023 年获批，共同构建了 siRNA 在肝脏疾病中的治疗版图。威廉・布莱尔高级分析师 Minter 指出："siRNA 在罕见病领域已展现变革性潜力，而更广泛适应症的突破才刚刚开始。"二、多器官靶向：从实验室到临床的突破尝试尽管现有 siRNA 疗法均聚焦肝脏，但多家药企已在非肝脏组织靶向中取得进展。Alnylam 首席技术官 Vasant Jadhav 表示，公司正攻关脑、脂肪、肺等组织的递送技术，其候选药物 mivelsiran 已进入 II 期临床试验，用于治疗脑淀粉样血管病，并启动阿尔茨海默病的 I 期研究。礼来的分子发现副总裁 Andrew Adams 强调，GalNAc 仍是目前最成功的靶向工具，但团队正探索脑靶向递送："一旦突破新组织的递送瓶颈，将开启类似肝脏靶向的适应症拓展浪潮。"Arrowhead Pharmaceuticals 的研究同样引人注目：其 siRNA 候选药物在小鼠实验中成功减少体脂并保留瘦肌肉，其中靶向脂肪细胞 ALK7 基因的疗法已启动早期临床；另一款靶向肺部的 ARO-RAGE 在哮喘患者中使目标蛋白水平降低 88%，展现出呼吸系统疾病的治疗潜力。三、技术边界与行业竞争格局siRNA 疗法仍面临固有挑战：无法完全敲除基因表达，仅能下调；且无法直接补充缺失蛋白。Jadhav 以 Givlaari 为例解释 workaround 策略：通过沉默代谢通路中上游的 GO 酶，降低急性肝卟啉症的毒性中间产物，而非直接修复突变酶。基因编辑技术的崛起也带来竞争压力。礼来的 Adams 指出，当 siRNA 长期数据证明敲低特定蛋白的安全性后，基因编辑可能成为永久性解决方案，如 Verve Therapeutics 已针对 PCSK9 基因开展编辑疗法的临床试验。但 Jadhav 强调 siRNA 的独特优势："兼具持久活性与可逆性，这是基因编辑无法同时实现的。"行业并购热潮反映了资本对 siRNA 的信心。2024 年 1 月，勃林格殷格翰与中国苏州瑞博生物达成 20 亿美元合作，开发非酒精性脂肪性肝炎（MASH）疗法；2025 年 5 月，GSK 以 12 亿美元收购 Boston Pharmaceuticals 的 FGF21 类似物，同样瞄准 MASH。据预测，到 2030 年 MASH 将影响 2700 万美国人，这类代谢疾病正成为 siRNA 的下一个战场。四、未来展望：技术迭代与市场扩容的双重机遇Minter 将 siRNA 的当前阶段形容为 "站在悬崖边缘"：一方面，肝脏靶向的成功奠定了坚实基础；另一方面，多器官递送的突破将开启黄金时代。Alnylam 设定了 2030 年 "靶向任意器官" 的目标，而礼来、Arrowhead 等企业的管线进展印证了这一愿景的可行性。从科学意义看，siRNA 不仅是药物开发的新工具，更重塑了基因调控的治疗逻辑 —— 通过 "基因开关" 而非传统小分子或抗体，实现更精准的疾病干预。随着递送技术的突破，神经系统、免疫系统等复杂疾病的治疗有望迎来革新。对患者而言，siRNA 的长效性（部分药物每半年给药一次）和高特异性，意味着更便捷的治疗方案和更少的副作用。而对行业来说，这场从肝脏到全身的技术跨越，可能催生数千亿美元的市场，重塑生物医药的竞争格局。站在 2025 年的技术临界点，siRNA 疗法的下一个十年注定充满挑战与机遇。正如 Minter 所言："未来五到十年，这个领域必将激动人心，我们正见证一场医学革命的序幕。" 当 Alnylam 等先驱者突破组织屏障，siRNA 或将成为继单克隆抗体、基因编辑之后，又一个改变疾病治疗范式的颠覆性技术。参考来源：https://www.biospace.com/drug-development/sirna-on-the-precipice-as-candidates-reach-beyond-the-liver识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

iStock, Love Employee As multiple companies vie to expand on Alnylam’s success in commercializing RNAi therapeutics, the pioneering company has set a goal of targeting small interfering RNA to any organ by 2030. In March, Alnylam chalked up two FDA approvals, for Amvuttra in transthyretin-mediated amyloidosis and, with Sanofi, Qfitlia in hemophilia A and B. Such approvals have become par for the course for Alnylam, leading multiple other companies—including GSK , AbbVie , Boehringer Ingelheim and Eli Lilly —to follow suit in pursuing therapies based on small interfering RNA (siRNA). And it’s not just the number of companies involved that’s expanding: while all siRNA therapies approved so far target the liver, Alnylam and others are now seeing some success in targeting other organs as well. The past two years have seen billions of dollars change hands in a bid to be part of this rapidly growing field. In January 2024, for example, Boehringer Ingelheim announced an agreement potentially worth more than $2 billion with Chinese biotech Suzhou Ribo Life Science and its Swedish unit Ribocure Pharmaceuticals to develop siRNA-based treatments for nonalcoholic or metabolic dysfunction-associated steatohepatitis (MASH), a disease expected to afflict 27 million Americans by 2030. And just last month, GSK plunked down $1.2 billion for Boston Pharmaceuticals’ investigational FGF21 analog efimosfermin alfa, also targeting MASH. “I think the siRNA space, for rare disease predominantly, has been revolutionary in a handful of cases,” said Myles Minter, a senior biotech analyst at William Blair. “And I do think that the large promise of the field to go into broader, more prevalent indications and to get more approvals is largely ahead of us.” A Genetic On/Off Switch The term RNA interference dates back to a 1998 paper by Craig Mello and colleagues, who found that double-stranded RNA was more effective than single strands in silencing genes with corresponding sequences in C. elegans . The mechanism turned out to also work in mammalian cells , and in 2002, multiple researchers who’d led key studies of the phenomenon, including Mello, teamed up with investors to found Alnylam. It took 16 years to gain FDA approval for the first siRNA drug, Onpattro, for polyneuropathy of hereditary transthyretin-mediated amyloidosis, a rare genetic disorder caused by mutations in the transthyretin ( TTR ) gene. One challenge Alnylam faced in the intervening years was in designing siRNAs that could escape degradation within the body for long enough to be effective, explained Vasant Jadhav, the company’s chief technology officer. But the biggest hurdle—one not unique to siRNAs—was getting the nucleic acid payloads where they needed to go. Then, in 2014, Alnylam researchers and their academic colleagues reported that linking siRNAs with a ligand called GalNAc would get them into cells in the liver, but not into other organs. Onpattro, approved in 2018, is a GalNac-linked siRNA. The drug “was pretty revolutionary at the time,” Minter said, because rather than simply treating symptoms or even slowing the toll of polyneuropathy of hereditary transthyretin-mediated amyloidosis, it elicited functional improvement. “The way I like to think about siRNA is that it’s a way that you can titrate, so you can dose at a genetic level. And it’s really one of the only modalities that you can do that with,” Minter told BioSpace . Other therapies followed from Alnylam for hypercholesterolemia (Leqvio, developed and commercialized by Novartis), acute hepatic porphyria (Givlaari) and primary hyperoxaluria type 1 (Oxlumo). Apart from Alnylam and its partners Sanofi and Novartis, the only other company to get an siRNA drug onto the market so far is Novo Nordisk, whose Rivfloza (nedosiran), approved by the FDA in 2023, treats the rare genetic disease primary hyperoxaluria type 1 (PH1). Testing the Limits So far, all of these therapies have targeted processes in the liver—including Amvuttra, which takes aim at cardiac outcomes via knocking down transthyretin (TTR) in hepatic cells. But experts who spoke with BioSpace said that could soon change. “Where we’re starting to see innovation—and it still is early stage, although it looks very promising—is trying to deliver to new tissues,” Minter said. That targeting problem is “the major question in the field that we’re working on right now.” Andrew Adams, Eli Lilly’s group vice president, molecule discovery and director of the Lilly Institute for Genetic Medicines, echoed this. GalNAc has thus far been a “unicorn” in the field in terms of its specific and safe delivery, and “we have a lot of work to do to open up si[RNA]beyond the hepatocyte, but . . . probably once we crack it is going to be similar to when Alnylam and others initially cracked GalNAc, and you’ll just sort of walk your way down the list of indications in the new tissue that you open up,” he told BioSpace . “I think probably the most interesting space for the field right now is in delivery to the brain and going after diseases of the brain,” he said, citing Alnylam’s candidate mivelsiran, currently in Phase II for cerebral amyloid angiopathy and Phase I for Alzheimer’s disease. Lilly, too, is pursuing neurodegenerative targets with siRNA, Adams added. Other tissues with promising early data include adipose and lung. In a March conference presentation, for example, Arrowhead Pharmaceuticals released mouse data on two siRNA candidates devised to reduce body fat while preserving lean muscle mass. One targets hepatic cells’ expression of a gene, INHBE , that is involved in metabolic processes, while the other silences expression of ALK7 , a gene needed for fat storage, in lipocytes. Early clinical studies on both candidates have begun. And last spring, Arrowhead announced interim results of a Phase I/II study of ARO-RAGE, an siRNA that targets lung tissue and silences the receptor for advanced glycation end-products, a mediator of type 2 inflammation. In study participants with asthma, two doses of the candidate reduced serum levels of the target protein by up to 88%, the company reported. siRNA’s limitations don’t end at targeting. It can’t be used to completely knock out expression of a gene, only knock it down, and it can’t by itself be used against multiple genetic targets, Jadhav noted. In addition, RNAi can only dial gene expression down, so it can’t be used to directly boost levels of a deficient protein. Researchers have found workarounds for this in some cases, though. Jadhav cited the example of Givlaari, which treats acute hepatic porphyria. “In this metabolic pathway, the heme biosynthesis, one of the enzymes is mutated, and because of that, you have toxic intermediates that build up,” he said. Since siRNA can’t replace the mutated enzyme, the therapy instead targets a different enzyme, GO, that’s upstream of the toxic intermediates, lowering their levels. siRNA’s successes could pave the way for a more permanent treatment option, Adams said. “Once you’ve generated enough evidence over a long enough period of time in enough patients that getting rid of this protein [via siRNA] has no negative consequences in an adult . . . Probably at that point you start to feel confident to permanently change something, but I think the bar should be and is high for things that people will tolerate permanent genetic changes for,” he said. He raised the example of Leqvio, which targets the enzyme PCSK9 in order to lower cholesterol levels. Verve Therapeutics now has a gene editor targeting the same enzyme in early clinical trials. Jadhav allowed that gene editing could become a competitor to siRNA in some cases. “I think at the end of the day, any solution . . . biopharma brings for the patients would be great,” he said. “At the same time, we feel that with RNAi, we can achieve [a] durable level of activity and still be reversible. You kind of get the best of both things. So we remain very confident and very optimistic about the future of RNAi.” Looking ahead, Minter summarized what he sees as the prospects for siRNA: “we’re at the precipice where we’re waiting, but it’s an exciting five to ten years ahead for the field, no doubt.”