University of Massachusetts

BridgeBio disclosed results Thursday from a Phase 1/2 study of its gene therapy for Canavan disease, an extremely rare and devastating genetic disorder that causes the brain’s white matter to break down. The body needs a gene called ASPA to code for a key enzyme that breaks down an amino acid called N-acetyl-L-aspartic acid — or NAA. In people with Canavan, that gene is mutated, leading to damage of the white matter in the brain. It’s estimated to impact roughly 1 in 100,000 births, more frequently in the Ashkenazi Jewish population. With the infantile-onset form of the disease, most patients don’t live into their teens. Thus far, BridgeBio has treated eight children with the lowest dose of its virus-based gene therapy, called BBP-812, as well as three children at a higher dose. After treatment, children who got the lower dose saw the levels of NAA in their urine go down by 64% on average, and those who received the higher dose saw an average 73% decrease. In the cerebrospinal fluid, children who got the lower dose saw an average 70% decrease in NAA measures. (Fluid changes in the three who received the higher dose weren’t reported.) The data were presented at the European Society of Gene and Cell Therapy. Participants, who were dosed at 0 to 30 months of age, also saw “clinically meaningful” improvements in motor skills. That “stands in stark contrast to the characterized natural history of the disease, where the trajectory over this time period is essentially flat,” BridgeBio said in its announcement of the results. The program stands out against an increasingly challenging backdrop for rare disease gene therapies, where other academic-developed programs that were handed off to drug companies have been shelved or stalled, as Endpoints News has previously reported . In this case, BridgeBio’s subsidiary licensed the gene therapy from UMass Chan Medical School, where it was developed by researchers led by professor Guangping Gao. For Canavan disease, the company hasn’t yet selected a dose, according to BridgeBio’s CEO of gene therapy Eric David. It expects to use the next part of the study — a 15-patient expansion cohort — to apply for accelerated approval with the FDA. BridgeBio plans to use NAA as a surrogate biomarker for accelerated approval. It will also compare the results of its trial to a natural history study of the disease. In September, BridgeBio announced that it wasn’t moving forward with its other gene therapy for congenital adrenal hyperplasia following data that were “not yet transformational,” according to CEO Neil Kumar, cutting its gene therapy budget by $50 million as a result.

▎药明康德内容团队编辑 “这像是真正诺贝尔委员会打来的电话！”这是今年新晋诺贝尔生理学或医学奖得主Gary Ruvkun博士在收到获奖通知时的第一反应。过去，他的同事曾多次恶作剧假装颁发诺贝尔奖给他，但这一次是真的！ ▲Victor Ambros博士与Gary Ruvkun博士（图片来源：诺贝尔奖官方网站） 天文学的科学启蒙 Ruvkun的童年是在1960年代的美国度过的，那时首颗通信卫星Echo发射，缓缓穿过旧金山湾区的上空，点燃了小Ruvkun的科学梦想。童年时，他沉迷于观看水星和双子座火箭发射的直播，收到了天文望远镜作为礼物，还在公共图书馆中钻研天文学书籍。他的父亲是一名土木工程师，在培养Ruvkun对天文学的早期兴趣中扮演了重要角色，激发了他对自然界的持续好奇。 Ruvkun对无线电的热爱逐渐引发了他对电子学的兴趣，但在加州大学伯克利分校求学期间，他发现自己对物理学更感兴趣，并于1973年获得生物物理学学士学位。然而，刚毕业的他并没有对学术研究充满热情，反而对未来充满了不确定性。Ruvkun生活的城市被视为嬉皮运动的发源地，他在一个经济、社会和政治动荡的年代成长，许多同龄人选择研究社会弊端，能在科学领域完成学业的实属罕见。 图片来源：123RF 本科毕业后“不务正业” 最终，他决定买一辆蓝白相间的面包车，开始沿着太平洋海岸的旅行。“我完全不知道自己要去哪里，”Ruvkun回忆道。在旅途中，他面试过核电厂的工作，还在电台尝试做DJ，最后在俄勒冈州的一个植树合作社找到了工作——这是他在酒吧闲聊时获得的机会。他在俄勒冈和华盛顿各地种植了约五万棵树，期间在车中生活，下班后与伐木工人一同饮酒。随后，一位朋友邀请他去南美洲旅行。“我们从墨西哥边境一路南下到阿根廷的火地群岛，再返回，走遍了各地，”他说。在一年的游历中，Ruvkun在玻利维亚的一个俱乐部偶然发现了一堆杂志。“我坐下来整整一天都在读《科学美国人》，”他说，“那是我一个月中最美好的一天。我心想，‘是时候回去了’。” 投身基因重组技术的革命浪潮 1976年，Ruvkun重返美国，开始了他的哈佛大学博士研究生涯。彼时，哈佛正处于基因重组技术革命的热潮中，Ruvkun毫不犹豫地投身其中。过去的植树工作和在发展中国家的旅行经历，也使他逐渐倾向于分子植物科学的研究。在Frederick Ausubel教授的指导下，他于1982年获得微生物遗传学博士学位，研究重点是如何敲除苜蓿根瘤菌（Rhizobium meliloti）中的固氮基因。由于当时科学家对根瘤菌这种“奇特微生物”的遗传机制远不如对大肠杆菌的了解，这是一项巨大的挑战。然而，Ruvkun研发的技术最终成功改变了多种细菌的基因，为他赢得了哈佛大学学者协会（Society of Fellows）的杰出青年研究员奖学金。 在随后的研究中，Ruvkun被“生命如何从一个受精卵发育为具有专门器官的生物体”这一重大问题所吸引，转向了发育生物学。他在哈佛生物物理学家、诺贝尔奖得主Walter Gilbert博士和麻省理工学院神经生物学家Robert Horvitz博士的实验室中进行了三年的博士后研究。在Horvitz博士的实验室中，Ruvkun第一次接触到未来将为他赢得诺贝尔奖的毫米级小生物线虫（C. elegans）。与同样获得今年诺贝尔奖的Victor Ambros博士合作，他们利用两种突变的线虫株检视基因调控在线虫发育中的作用。 ▲Ambros博士与Ruvkun博士使用线虫共同合作研究miRNA（图片来源：参考资料[4]） 首次发表miRNA相关论文 1985年，Ruvkun被任命为哈佛大学的新任助理教授，并在波士顿的麻省总医院建立了自己的实验室，持续专注于线虫的发育遗传学研究。同时，Ambros也在哈佛大学建立了自己的实验室。1993年，两人共同合作在顶尖学术期刊《细胞》上首次发表了关于微RNA（miRNA）的论文，发现lin-4这种miRNA可以与其目标基因lin-14进行碱基配对结合，从而调控其翻译，而这种结合发生在折叠RNA中常见的环和突起上。然而，这一重大发现当时并未引起科学界的广泛关注，科学家普遍认为这只是线虫特有的基因调控机制，与其他动物和人类关系不大。 直到2000年，Ruvkun实验室识别出了第二个miRNA let-7。与lin-4不同的是，Ruvkun的研究团队证明let-7 miRNA的序列高度保守，存在于整个动物界。这篇论文引起了广泛关注，数十个实验室随后相继发现了不同的miRNA。如今，我们知道人类拥有超过一千种不同的miRNA基因，miRNA在多细胞生物中的基因调控作用被广泛认可，并已应用于临床肿瘤分型，发现与心脏病、病毒致病机制、神经功能与疾病调节，以及从全能干细胞向分化细胞转变等过程相关。 ▲miRNA let-7在许多动物中高度保守（图片来源：参考资料[4]） 只想着拿终生教职... 当诺贝尔委员会采访Ruvkun，询问他和Ambros在发布首篇miRNA论文时是否意识到这是项“诺贝尔奖级”的发现时，Ruvkun却表示：“不不不，那时我们只觉得自己正在进行一些奇特而有趣的工作。我们当时只是年轻的教职员，只想确保能够顺利迈向职业生涯的下一个阶段。我们从未想过这会赢得诺贝尔奖，只是觉得这真的很有趣。”然而，随着他观察miRNA领域的蓬勃发展，他逐渐意识到miRNA这个领域的开启确实是一个可能获得奖项和认可的重大变革，尽管这个过程漫长，他对此感到无比欣喜，尤其是能够吸引杰出人才在这个领域进行研究，并与两三百人进行学术讨论更是让他倍感激动。 和学生“赌博”的亲民导师 在私底下，Ruvkun也是一位关心学生的亲切导师。马萨诸塞大学医学院教授、Ruvkun的前研究生Heidi Tissenbaum博士曾这样形容她的诺贝尔得主导师：“无论何时，你需要与他谈话，他的门总是敞开的。”在Tissenbaum研究生期间，请假三个月生孩子——这一在哈佛几乎前所未闻的事情时，Ruvkun给予了她极大的支持，甚至告诉她不用担心论文工作。此外，Ruvkun不仅对科学充满热情，激励着团队，还使实验室的氛围活泼。在实验室会议上，他总是与学生和博士后就理论和实验打赌。“人们提出各种想法，他会说，‘好吧，三美元的赌注，’”Tissenbaum回忆道。 科学的流浪者，持续探索火星生命 尽管Ruvkun因miRNA的重大发现赢得了无数奖项与荣誉，但他从未忘记过最初对天文学的好奇。除了在实验室工作外，Ruvkun还会在业余时间阅读天文学、地质学和行星科学的书籍，甚至曾启动一项“疯狂”的计划——利用聚合酶链反应（PCR）在火星上寻找生命。在哈佛火星项目中，Ruvkun与同事们设计了一种小型机器人PCR检测器，能够现场放大和测序任何存在于外星土壤中的DNA，希望借此检测火星土壤样本中的古代核糖体RNA基因序列，这些序列在地球上已知的所有生命形式中都是保守的。 ▲Ruvkun博士与其妻女在获得诺奖通知时的合影（图片来源：参考资料[2]） Ruvkun在接受《科学》杂志的采访时曾表示，像他这样的遗传学家之所以在科学上保持年轻，是因为会不断接触到新领域。他说，他从来不知道下一个实验会把他带到哪里，但这没关系。事实证明，科学研究与流浪者的生活并没有太大区别，“这就像是跳上一辆公交车，看看它会开往哪里。” ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] First reactions. Telephone interview, October 2024. Retrieved October 7, 2024 from https://www.nobelprize.org/prizes/medicine/2024/ruvkun/interview/ [2] Gary Ruvkun Shares Nobel Prize in Medicine. Retrieved October 7, 2024 from https://www.harvardmagazine.com/2024/10/gary-ruvkun-nobel-prize-winner-medicine [3] The drifter. Retried October 7, 2024 from https://www.science.org/content/article/drifter [4] Press release. Retrieved October 7, 2024 from https://www.nobelprize.org/prizes/medicine/2024/press-release/ [5] Gary B. Ruvkun. Retrieved October 7, 2024 from https://dms.hms.harvard.edu/people/gary-b-ruvkun 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Physiology or Medicine Prize award honors discovery of small regulatory RNAsBoston, MA, Oct. 07, 2024 (GLOBE NEWSWIRE) -- Media notice: a press conference with Dr. Ruvkun will be held at the MGH Richard B. Simches Research Center, located at 185 Cambridge Street in Boston, at 10:30 am ET. The event will also be streamed live: https://partners.zoom.us/j/88343479443?pwd=Q5GuisCyvhpAb4p4ltYNKq7886ucoG.1 Massachusetts General Hospital (MGH) and Harvard Medical School investigator Gary Ruvkun, PhD, has been named a recipient of the 2024 Nobel Prize in Physiology or Medicine for his role in the discovery of microRNA and its role in post-transcriptional gene regulation. He shares the award with his collaborator Victor Ambros, PhD, of the University of Massachusetts Medical School. Instead of being translated into proteins, as messenger RNAs are, the hundred-times-smaller microRNAs block gene expression by binding to regulatory segments in their target messenger RNAs. Current knowledge suggests that most plant and animal genomes, including the human genome, contain more than 1,000 microRNAs, which control many protein-coding messenger RNAs and may be involved in a broad range of normal- and disease-related activities. Human microRNAs have been implicated in heart disease, in viral pathogenesis and in regulation of neural function and disease. Human therapies based on microRNAs are in clinical trials for heart disease, cancer, neurodegenerative diseases, and more. The pair began investigating genes that control development in the C. elegans roundworm. As fellows at Massachusetts Institute of Technology, they worked together to isolate a gene called lin-14 that operates in concert with a gene called lin-4 to regulate the transition through key developmental stages. After establishing his own laboratory in the MGH Department of Molecular Biology, Ruvkun continued collaborating with Ambros – then at Harvard – to uncover how the two regulatory genes interacted. They discovered that lin-4 did not block the activity of lin-14 through the protein for which it coded, but in a manner never seen before by direct interaction between the two genes’ RNA strands. The lin-4 RNA was also much smaller than any other RNA that previously had been studied, 22 nucleotides long. In 2000, Ruvkun’s team discovered the second microRNA, let-7, that shuts down its target mRNA by base pairing to it in the same way that lin-4 silences lin-14. The Ruvkun lab also discovered that diverse animals, ranging from flies to fish to humans, have a let-7 microRNA that exactly matches the C. elegans let-7 microRNA, implying that this mechanism of translational regulation was present in the common ancestor to all animals and has been maintained by natural selection since these species diverged almost a billion years ago. These findings established that microRNAs are universal to animals and not unique to C. elegans. Over the past two decades, research into the potential of microRNAs for the diagnosis, prognosis and treatment of disease has expanded from the two original papers published by Ruvkun and Ambros in 1993 to 176,000 papers today. In addition to continuing investigation of microRNA’s role in controlling gene expression, Ruvkun’s team studies other mechanisms involved in the development, metabolism and longevity of C. elegans, including genes involved in the regulation and storage of fat. In 2016, his team identified molecules essential to the ability of C. elegans cells to recognize dysfunction of the proteasome, a cellular component that degrades unneeded or defective proteins, findings that may be applicable to important human neurodegenerative diseases. It is significant, Ruvkun notes, that unlike the majority of U.S. university and hospital research units, the MGH Department of Molecular Biology fully supported his research expenses during the decade when this research was initiated. Over the next decade, MGH-supplied research funds supported half of Ruvkun’s research budget. Much of the departmental research support was the result of a unique funding relationship between MGH and the German chemical company Hoechst AG. Ruvkun wishes to acknowledge how much this unique research support by his home institution empowered his research program. Ruvkun is a professor of Genetics at Harvard Medical School, an investigator at the MGH Department of Molecular Biology and a member of the MGH Research Institute. He holds a bachelor’s degree in Biophysics from the University of California at Berkeley and a PhD in Biophysics from Harvard University. In 2008 Ruvkun, Ambros and David Baulcombe of the University of Cambridge received the Lasker Award for Basic Medical Research for the work currently being honored. Among the many other awards Ruvkun has received – some shared with Ambros and Baulcombe – are the Franklin Medal, the Gairdner International Award, the 2012 Paul Janssen Award for Biomedical Research, the 2014 Gruber Genetics Prize, the 2015 Breakthrough Prize in Life Sciences, the 2016 March of Dimes Prize and the 2008 Warren Triennial Prize from MGH. A member of the National Academy of Sciences, Ruvkun has co-led a NASA-funded Search for Extraterrestrial genomes, which has proposed using DNA sequencing techniques, commonly used to detect and classify organisms here on Earth, as part of the search for life on Mars or other planets. About Massachusetts General Hospital Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. MGH is a founding member of the Mass General Brigham healthcare system.