原文： Scientists have successfully stopped a pig kidney from being rejected by its human recipient. The organ survived for 61 days in the recipient, a 57-year-old brain-dead man in the United States, the longest a genetically modified pig organ has survived in a brain-dead person. In two papers published in Nature today, researchers describe the main factors that cause the human immune system to reject transplanted organs. Researchers say the findings will improve outcomes for living people who receive organs from other people, or from animals. “In my mind, this is the first evidence of how to reverse rejection,” says Muhammad Mohiuddin, a clinician researcher at the University of Maryland School of Medicine in Baltimore, who led the first pig-heart transplant into a living person in 2022. In the past three years, around a dozen living people have received organs from genetically modified pigs, including hearts, kidneys, livers and a thymus. But most of these organs were eventually removed after losing function or no longer providing enough benefit to justify the immunosuppression treatment required. Other recipients died shortly after the transplant. Along with the pig kidney, the male recipient also received the pig’s thymus, a small gland that taught the man’s immune system to recognize the pig’s cells as part of the body. The thymus probably played a big role in helping the pig organ survive for longer, says co-author of the studies, Robert Montgomery, a surgeon and researcher at the New York University Langone Transplant Institute in New York City. In past experiments with non-human primates, he says, the modified kidney survived better when transplanted with the thymus than without it. Avoiding rejection The latest pig-organ transplant was performed on 14 July 2023 at New York University Langone in New York City. The kidney and thymus were taken from a pig supplied by Revivicor, a subsidiary of biotechnology firm United Therapeutics, based in Virginia. The pigs had a single genetic modification, removing gene GGAT1, to stop the production of a sugar called alpha-gal on cells. Alpha-gal has been found to cause organ rejection in transplant surgeries in non-human primates. Immediately after the transplant, the kidney appeared healthy and produced urine. But 33 days after the procedure, the kidney’s function suddenly declined, and a biopsy showed that the organ was being rejected and damaged by antibodies. The team replaced the person’s plasma and gave them steroids and a drug called pegcetacoplan, which stopped pig cells being tagged for destruction by the immune system. But on day 49, another biopsy showed a different type of rejection, in which inflammatory cells had infiltrated the kidney’s surface. This was treated with an immunosuppressant that destroys T cells and stopped the organ from being rejected. Kidney function was also fully restored. The research team chose to end the experiment at 61 days. Immune system investigation Following the transplant, the team also analysed the person’s blood to map how the immune system responded on a molecular level. They showed that the pig kidney increasingly expressed genes associated with rejection, such as CXCL9, CXCL10 and CXCL11, and their expression decreased after the rejection was stopped. High levels of macrophages and natural killer cells, a type of T cell, which are part of the innate immune system, were observed on day 33. Mohiuddin says this suggests that T cells play a more prominent role in rejection than was previously thought. He adds that analysing the transplant recipient’s blood could help clinicians to identify and treat rejection early. Montgomery says the case could also inform which pig genetic modifications are necessary. Most pig organs come from pigs that have had at least 10 genetic modifications to reduce the risk of rejection. Montgomery says only removing GGATI was enough to prevent immediate organ rejection. Scientists can breed pigs with this modification, whereas pigs with multiple modifications need to be cloned, he adds. But Montgomery and his colleagues acknowledge that the efficacy of using organs from pigs with minimal genetic edits needs to be validated in further experiments in brain-dead and living people. His team are working on clinical trials with United Therapeutics. They have previously transplanted a kidney with the same modification into one living person, which failed within two months owing to the recipients’ pre-existing heart failure. 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。 本期制作：Gilly 热爱可抵岁月漫长～

摘要：2025年4月3日，加州大学旧金山分校的神经生物学家们发表了研究性文章，他们发现雌性小鼠脑脊膜调节性 T 细胞 (mTreg cells) 能够抑制痛觉反应，其机制是：脑脊膜调节性 T 细胞产生的内啡肽 (opioid enkephalin) 通过 MrgprD+ 神经元表达的delta opioid 受体发挥抗伤害性感受作用。 Text: Unlike the combative immune cells that protect us from pathogens, regulatory T cells (Tregs) are nurturers. They salve inflammation, promote healing of injured tissue, and rein in immune attacks to curb self-inflicted damage.Now, a study of mice reported today in Science suggests some Tregs also act on nerve cells to quell a specific type of pain—but only in females. Why only female rodents seem to benefit remains unclear, but researchers hope they might someday enlist these Tregs to address pain conditions, many of which disproportionately affect women. “It’s a very impressive paper,” says neuroscientist Gila Moalem-Taylor of the University of New South Wales Sydney, who wasn’t connected to the research. The study “uses elegant, sophisticated methods to conclusively demonstrate the mechanisms” by which the cells reduce one kind of sensitivity to pain, she says. Tregs, a type of white blood cell, are best known for their role in keeping the immune system in balance and preventing autoimmunity. But researchers have recently found that they also help control pain. For example, a 2021 study by neuroscientist Allan Basbaum of the University of California San Francisco (UCSF) and colleagues showed that Tregs reduce mice’s sensitivity to pain triggered by other immune cells that reside in the brain and spinal cord. That research and additional work suggested Tregs influence pain by targeting various immune cells and tamping down inflammation. But these studies left open the possibility that Tregs might also directly affect pain-sensing nerve cells. Basbaum, his postdoc Élora Midavaine, UCSF dermatologist Sakeen Kashem, and their colleagues launched the new study to nail down how the regulatory cells curb pain. They focused on Tregs that dwell in the meninges—the membranes that sheathe the brain and spinal cord—and in similar nearby membranes. The cells are much more abundant in these structures than elsewhere in the nervous system. To find out whether the cells affect pain perception, the scientists used genetically engineered mice whose Tregs are vulnerable to a toxin produced by the bacteria that cause diphtheria. Injecting this toxin into the meninges in the lower back killed about 90% of the Tregs in the membranes without harming Tregs in the rest of the body. The scientists then measured the animals’ responsiveness to pain by prodding their feet with hairlike fibers of varying flexibility. The stiffer the fiber necessary to induce a mouse to pull its foot away, the lower the animal’s presumed sensitivity to pain. In female mice, the researchers found, culling Tregs in the meninges caused pain sensitivity to shoot up. Loss of Tregs did not have the same effect in male mice, however, and it didn’t alter either sex’s responsiveness to heat, cold, and other types of painful stimulation. Boosting Tregs, on the other hand, appeared to blunt painful stimulation. In mice with higher pain sensitivity because of nerve damage, increasing the number of Tregs with injections of the immune system protein IL-2 counteracted this hypersensitivity—but again, only in females. To further probe this sex-specific effect, the researchers surgically removed the ovaries from female mice or gave them a drug that blocks the effects of estrogen. In both cases, IL-2 did not reduce pain sensitivity. The researchers’ findings suggest female sex hormones somehow help control the pain-reducing functions of Tregs. Previous work revealed that Tregs pump out pain-suppressing molecules known as enkephalins. By performing bone marrow transplants with genetically engineered stem cells, the researchers produced mice in which the diphtheria toxin could kill blood cells that made enkephalins while sparing other body cells that fashioned the signaling molecules. Shots of the toxin caused the number of Tregs in the animals to fall and their pain sensitivity to rise. …（行文至此，加入听友群，可获得完整文稿和文章解读） 原文链接：www.science.org 研究来源： www.science.org 词汇：nurturer n. 养育者；salve v. 缓和；rein v. 约束；curb v. 控制；self-inflicted adj. 加于自身的；quell v. 减轻；disproportionately adv. 不成比例地；tamp down 抑制；dermatologist n. 皮肤学者; nail down 确保某事发生; sheathe v. 覆盖；vulnerable adj. 易受伤害的；diphtheria n. 白喉；prod v. 刺；cull v. 选择性杀死；shoot up 迅速上升；estrogen n. 雌性激素；pump out 频繁地生产某物；enkephalin n. 内啡肽；spare v. 使…不受伤害 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。 本期制作：Gilly 热爱可抵岁月漫长～

摘要：2025年4月2日，Denali Therapeutics 宣布已经启动递交 Tividenofusp Alfa（DNL310）的加速批准上市申请，用于治疗亨特氏综合征（MPS II）。 text: After some high-profile crashes, the one-time biotech darling is inching toward success with its Hunter syndrome treatment, which today began a rolling BLA for accelerated approval. Denali Therapeutics has its wheels on the fast track. The company initiated a biologics license application Wednesday for accelerated approval for Hunter syndrome treatment tividenofusp alfa (DNL310). It’s been a long time coming for Denali, which launched in 2015 with what was then the largest first-round venture financing in biotech history, a whopping $215 million. But a decade later, Denali doesn’t yet have an approved product, and its stock has dipped from its 2020 peak of more than $85 to just over $12 today. “When we came out of stealth in 2015, we raised a significant amount of money,” Carole Ho, Denali’s chief medical officer and head of development, told BioSpace. “And there was a question: What were we doing differently?” The brand-new company trumpeted a lofty goal of deploying new approaches to tackle neurodegenerative diseases—by targeting newly discovered genes tied to degenerative brain diseases. A year after launching, Denali scored another $130 million in a series B round led by Genentech veterans and maintained all of its founding investors. The company signed a bevy of research agreements, including deals with Blaze Bioscience and the Fred Hutchinson Cancer Research Center, to work on one of neurology’s toughest problems: getting drugs across the blood-brain barrier (BBB). Now, Denali is eyeing the culmination of these approaches with DNL310, an enzyme-replacement therapy that rides a specialized transport vehicle across the blood-brain barrier. The therapy secured FDA Breakthrough Therapy Designation in January, adding to a list of honors already held by the drug, including Fast Track Designation, Orphan Drug Designation and Rare Pediatric Disease Designation. “All of this suggests the agency’s enthusiasm for the molecule,” Ho said. Stifel analysts responded to the BLA submission Wednesday morning, saying, “We’re potentially nearing the end of an up-and-down regulatory path for [DNL310], where DNLI was finally able to align with FDA’s CDER on leveraging CSF heparan-sulfate (HS) as a surrogate biomarker for the basis of accelerated approval.” Stifel also noted the turbulent times in which this application has been submitted. “Notably, this announcement comes amidst significant turnover at FDA, where several senior directors across both CBER/CDER have departed,” the analysts wrote. ……（节选至此，加入听友群，可获得完整文稿，并为你解答该药物的设计原理） 原文链接：https://www.biospace.com/drug-development/denali-goes-all-in-on-neurosciences-thorniest-hurdle-crossing-the-blood-brain-barrier 药物原理： DNL310 运用 ETV 递送透过血脑屏障 引自：https://www.denalitherapeutics.com 词汇：thorny adj. 棘手的；high-profile adj. 备受瞩目的；inch v. 缓慢移动；BLA, biologics license application abbr. 生物制剂许可申请；whop adj. 巨大的；dip v. 下降；come out 首次亮相；stealth n. 隐身；trumpet v. 鼓吹；lofty adj. 高远的；launch v. 启动；bevy n. 一堆东西；culmination n. 最终结果；pediatric adj. 小儿科的；heparan-sulfate n. 乙酰肝素；surrogate adj. 替代的 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。 本期制作：Gilly 热爱可抵岁月漫长～

text: 粗体英文词汇附有中文释义喔～ Merck continues to build the case for the pulmonary arterial hypertension drug that won FDA approval in 2024. In high-risk patients with pulmonary arterial hypertension(PAH), Merck’s fusion protein therapeutic Winrevair reduced the likelihood of major morbidity and mortality by 76% in the Phase III ZENITH trial. Analysts at Guggenheim Partners called this outcome “striking” and “very impressive” in a note to investors Monday, pointing to improvements in key secondary outcomes in overall survival and transplant-free survival. The Guggenheim analysts also pointed out that Winrevair had “relatively consistent improvements” in mortality and morbidity across patient subgroups, including age, sex and disease subtype and severity. In November 2024, Merck announced that, following the recommendations of an independent data monitoring board, it was stopping ZENITH ahead of schedule due to “overwhelming efficacy.” On Monday, the pharma revealed that in the Winrevair arm, 17.4% of patients experienced at least one major morbidity or mortality event, as opposed to 34.7% of placebo comparators. The data were (这里误读为was) presented at the 2025 American College of Cardiology’s Annual Scientific Session and Expo and simultaneously published in The New England Journal of Medicine. Winrevair is a recombinant activin receptor type II A-Fc fusion protein that targets and binds to activin A and other ligands that belong to the TGF-β superfamily. This mechanism of action allows Winrevair to restore balance to vascular proliferation, a key pathway that is altered in PAH. In particular, PAH patients see high excessive cell proliferation in key arteries, leading to thickened blood vessel walls and, in turn, impaired blood flow. Winrevair was approved by the FDA to treat PAH in March 2024, making it the first-ever drug for the disease that targets activin signaling. Merck continues to build its evidence base for Winrevair. In March 2023, the pharma unveiled full data from the Phase III STELLAR trial, touting a 40.8-meter improvement in 6-minute walk distance in patients with PAH following treatment with the drug. Winrevair also cut the risk of death or clinical worsening by 84% versus placebo. Merck is also running the Phase III HYPERION study to assess the benefit of Winrevair when used with background therapy. In January 2025, the company ended the trial ahead of schedule, in line with the recommendations of an external committee, because of strong efficacy findings in an interim analysis. Results from HYPERION will be presented later this year, according to Merck’s Monday announcement. 原文链接：https://www.biospace.com/drug-development/mercks-winrevair-cuts-morbidity-mortality-risk-by-over-75-in-phase-iii-pah-study 药物原理： Sotatercept 商品名为 Winrevair，是一种融合蛋白，由 human activin receptor type IIA（ACTRIIA）的胞外结构域和人类免疫球蛋白 G1 的 Fc 结构域组成。索塔特肽（Sotatercept）作为一种配体陷阱发挥作用，能够捕获 TGFβ 超家族的成员，从而恢复促增殖的 ACTRIIA 通路与抗增殖的 BMPR2 通路之间的平衡。 Ghofrani, HA., Gomberg-Maitland, M., Zhao, L. et al. Mechanisms and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 22, 105–120 (2025). doi.org 词汇：pulmonary adj.肺的；arterial adj.[解剖] 动脉的；hypertension n.高血压；morbidity n.发病率；mortality n.死亡率；placebo n.安慰剂；comparator n.对照组；thicken v.变厚；unveil v.公开；tout v.吹捧；interim n.阶段性成果 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。 本期制作：Gilly 热爱可抵岁月漫长～

text: Eli Lilly’s Alzheimer’s drug Kisunla has failed to get support from the European Medicines Agency over serious side effects and three patient deaths. The agency’s human medicines committee (CHMP) recommended that the European Commission reject Lilly’s donanemab, branded as Kisunla, saying its benefits don’t outweigh the risks of potential swelling and bleeding in the brain, called amyloid‑related imaging abnormalities (ARIA). The opinion marks another blow for anti-amyloid treatments in Europe. CHMP only recently gave the go-ahead for Eisai and Biogen’s Leqembi in November, after previously rejecting the drug over safety issues in July 2024. The regulator rejected Biogen’s Aduhelm in 2021, leading the company to withdraw its application a year later. The EC has the final say over new drug approvals, but it normally follows CHMP’s recommendations. CHMP has been wary of recommending Alzheimer’s drugs that risk the development of ARIAs. Kisunla has higher rates of ARIA compared to Leqembi. Both Aduhelm and Leqembi are FDA-approved, and Lilly won approval for Kisunla in the US last July. William Blair analysts view the Kisunla rejection as “unsurprising” given Leqembi’s initial rejection. But unlike CHMP’s decision to then give a positive opinion for Leqembi, there is a “real risk” that Kisunla may not make European approval given its higher rate of ARIAs. This can only be a win for Biogen and Eisai, the analysts said. ARIAs were recorded in 36.8% of people who took Kisunla compared with 14.9% who received the placebo, which resulted in three patient deaths, CHMP said in its latest opinion. Lilly said Friday it was “disappointed” by the CHMP’s decision and will look for a “re-examination” from the agency. The company has 15 days to submit for another review process. Kisunla is estimated to pull in around $2 billion in global sales in 2030, according to GlobalData analysts. Lilly’s application to CHMP used data from 1,736 patients enrolled in a Phase 3 study called TRAILBLAZER-ALZ 2, which was used to secure approvals in other markets including the UK, Japan, and China. Kisunla is given to a patient through an infusion drip once every four weeks and contains a monoclonal antibody that attaches to plaques that are formed in the brain in patients with Alzheimer’s disease. 原文链接：https://endpts.com/european-regulator-rejects-lilly-alzheimers-drug-over-side-effects/ 原文注释： Eli Lilly’s Alzheimer’s drug Kisunla 美国制药公司礼来（Eli Lilly）的阿尔茨海默病药物donanemab（商品名为Kisunla）是一款通过静脉注射的单克隆抗体药物，旨在清除大脑中导致阿尔茨海默病的淀粉样蛋白斑块，从而缓解早期阿尔茨海默症患者的认知能力丧失‌‌。2024年7月2日，美国食品药品监督管理局（FDA）正式批准美国礼来公司的新药Kisunla上市。 Eisai and Biogen’s Leqembi 由卫材（Eisai）与渤健（Biogen）联合开发的Leqembi，是一种抗体药物，主要用于治疗阿尔茨海默病。2024年8月23日，卫材和渤健宣布，其联合开发的阿尔茨海默病疗法Leqembi（lecanemab）已获得英国药品和健康产品管理局（MHRA）的上市许可。该疗法适用于治疗携带或不携带APOE E4等位基因的阿尔茨海默病（AD）引起的轻度认知障碍（MCI）和轻度痴呆成人患者。 ‌Biogen’s Aduhelm Aduhelm是一种靶向β淀粉样蛋白的单克隆抗体药物，主要用于治疗阿尔茨海默病。Aduhelm是自2003年以来获批用于阿尔茨海默病的首个新型疗法，是首个针对阿尔茨海默病潜在病理生理学的治疗药物，即大脑中存在β淀粉样蛋白斑块。 词汇：swelling n.肿块；amyloid n.淀粉样蛋白；blow n.打击；EC abbr.欧洲药品管理局；wary adj.谨慎的；placebo n.安慰剂；infusion n.输液 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。 本期制作：Gilly 热爱可抵岁月漫长～

text： Compounded versions could make up as much as 40% of the semaglutide market, said Novo Nordisk CEO Lars Fruergaard Jorgensen on Thursday, but the company hopes to win patients over. Novo Nordisk CEO Lars Fruergaard Jorgensen says U.S. drug compounders are harming the Danish pharma’s lucrative weight loss business and violating its intellectual property. Moreover, patients may not even know they are not getting the real thing. “There’s only one semaglutide. That’s what is in our products and patients should really check the product before they inject it,” Jorgensen said during an investor presentation Thursday. These compounded versions of the drug, which is marketed by Novo as Wegovy for weight loss and Ozempic for diabetes, could make up as much as 40% of the market, Jorgensen said. He added that Novo has tested some of the compounded semaglutide products and found impurities and banned substances. “The thought that in the U.S., you can have active pharmaceutical ingredient coming from overseas sources and then have local pharmacies, compounders make products available for patients that are not FDA approved is quite scary,” Jorgensen said. He noted that these products are, in the company’s view, illegal. Semaglutide was added to the FDA’s shortage list in 2022. This allowed compounding pharmacies to step in and manufacture product while Novo expanded manufacturing and boosted supply. But the drug was removed from the list in February and compounders were ordered to phase out the products. Jorgensen said the pharmacies have until late May to stop bulk compounding. “I sincerely hope many of those patients will then come back to Novo Nordisk,” the CEO said. To ensure they do, Novo is stepping up commercial efforts to educate patients and doctors. Jorgensen admitted that compounders are “damaging our business.” The company is working closely with the FDA on the issue, and the CEO noted that even the FBI has been shutting down compounders, while efforts in border control are underway. The company is also taking legal action against the compounders, who have sued the FDA over the removal of semaglutide and Eli Lilly’s rival med tirzepatide from the shortage list. “We hope that we will see the turn of compounding because of safety for patients,” Jorgensen said. “But of course, also that we have the patent-protected product that we have invested in developing it, and we would like to have the business for as long as it is patent-protected and then others can move in afterwards.” 原文链接：https://www.biospace.com/business/theres-only-one-semaglutide-novo-ceo-admits-compounders-are-hurting-weight-loss-business 背景介绍： 在美国，司美格鲁肽（semaglutide）于 2022 年被列入美国食品药品监督管理局（FDA）的短缺清单，这使得配制药房能够介入并生产相关产品。正是这些药房或制剂商的复方制剂损害了这家丹麦制药公司-诺和诺德（Novo Nordisk）在减肥领域颇具盈利性的业务。 原文注释： semaglutide 司美格鲁肽，丹麦诺和诺德公司研发的药物，属于一类被称为胰高血糖素样肽 - 1 受体激动剂（GLP-1 RAs）的药物，它模拟进食后由肠道释放的 GLP-1 激素。GLP-1 的一项作用是促使身体分泌更多的胰岛素，从而降低血糖（葡萄糖）。因此，司美格鲁肽可用于治疗 2 型糖尿病（商品名为Ozempic）。较高剂量的司美格鲁肽还会与大脑中抑制食欲的部分相互作用，它能够促使肥胖或超重人群减重，用作减肥药（商品名为Wegovy）。Ozempic和Wegovy是剂量不同的司美格鲁肽药物。 tirzepatide 替尔泊肽（商品名为Zepbound），是美国礼来公司（Eli Lilly and Company）研发成功上市的一种新型的GIP（胃抑制多肽）和GLP-1双受体激动剂，靶向治疗糖尿病、非酒精性脂肪性肝炎（NASH）和慢性体重管理。 词汇：lucrative adj.获利多的；impurity n.杂质；pharmaceutical adj.制药的；phase out 逐步淘汰；step up 提高；patent n.专利 本期制作：Gilly 欢迎大家在评论区与我互动，给我写邮件1978500617@qq.com，或加入听友群 Daily Life Science group 1 欢迎大家关注我的小宇宙读书播客《启真书汇》，将陆续更新政治历史、经济金融、管理学、哲学、心理学和社会学等书籍的深度解读，月更。 欢迎大家关注我的微信公众号《思无涯-Gilly》，代谢与免疫前沿研究文献深度解读，月更。