University of California, Davis

撰文 | 亦 人类与其他灵长类动物在大脑上存在显著差异，特别体现在新皮层的扩展和神经元连接的复杂性增加【1】。尽管之前的研究发现了一些关键基因，如FOXP2【2,3】和NOTCH2NL【4,6】，但大多数人类特异性重复基因尚未被发现或研究。造成以上现象的主要原因是基因组重复区域难以准确组装和分析，导致基因注释缺失和功能研究匮乏。 近日，来自加州大学戴维斯分校的Megan Y. Dennis团队在Cell上发表了文章Human-specific gene expansions contributeto brain evolution。利用首个端粒到端粒（T2T-CHM13）人类基因组，系统鉴定人类特异性复制基因，并解析其在脑进化中的作用。 作者首先基于 T2T-CHM13 基因组，筛选>98% 同源性的片段重复区域（SD98，97.8 Mbp），发现1,793个 SD98 基因（含 698个编码基因），其中 37% 在 GRCh38 中被遗漏或错误注释。而后结合基因注释、拷贝数分析和黑猩猩基因组比对，系统性鉴定人类特异性复制基因，定义 213 个人类特异性/扩增基因家族。为系统性鉴定人类特异性复制基因的变异模式，作者利用k-mer 旁系同源特异性拷贝数分析与古人类基因组做对比，发现13个基因仅存在于智人，15个基因受强纯化选择（皮层神经元迁移和突出形成有关的SRGAP2C），9 个受平衡选择（如T细胞抗原CD8B）。 接下来作者将重复基因变异与神经表型相关联，通过整合GWAS 目录、UK Biobank 和自闭症队列数据，作者鉴定了341个可能与大脑相关表型存在潜在联系的旁系同源基因，其中22个在自闭症患者中发生新生CNVs，18个位于自闭症相关热点的基因在患者中parCN显著异常。为研究人脑发育中重复基因的作用，作者分析了胎儿脑、类器官、神经干细胞等的转录组，发现58%拷贝数受限基因在发育脑表达，显著高于非受限基因。GO分析显示，B-turquoise模块（76个重复基因）调控神经元投射，而C-blue模块富集突触形成基因（如SRGAP2C），与自闭症风险基因共表达。通过建立小鼠和斑马鱼跨物种模型，作者进一步锁定了76个小鼠和41个斑马鱼直系同源基因，发现GPR89B等基因在三物种脑发育中表达模式保守，GPR89B过表达促进神经前体增殖，而FRMPD2B的截短蛋白拮抗全长功能，导致突触信号异常。 随后作者开始解析神经发育候选基因的遗传变异特征及选择信号。通过对144个个体（覆盖5大祖先群体）的13个候选基因家族深度测序，并整合HPRC/HGSVC组装数据，作者发现11个强约束基因（如SRGAP2C）无功能丧失突变，提示其必需性。而其他基因存在选择模式分化，如祖先旁系同源基因（如GPR89A）比衍生基因（如GPR89B）受更强纯化选择，与T细胞免疫调节相关的基因CD8B则被发现在欧洲人群中平衡选择。利用CRISPR敲除技术，作者在斑马鱼双模型中进行了基因功能的验证，证实了GPR89B促进神经前体细胞增殖，而FRMPD2B上调突触信号。进一步的机制解析发现，GPR89B起源于470万年前的GPR89A复制，通过延迟表达延长神经前体增殖期，可能驱动新皮质扩张，与1q21.1缺失/重复导致小头/大头畸形有关。而FRMPD2B是截短蛋白，缺失FERM/KIND域，通过拮抗全长FRMPD2，增强NMDA受体介导的突触可塑性，在出生后表达，避免胎儿期抑制导致的微头畸形。 总的来说，文章提供了最全面的人类复制基因目录，包括213个人类特异性基因家族，1002个旁系同源基因，一些同源基因如CD8B呈现出显著的选择特征。通过群体遗传学分析，发现148个基因家族可能驱动人类大脑进化。并提出GPR89B 剂量效应（促进神经祖细胞增殖）和 FRMPD2B 拮抗模型（改变谷氨酸突触可塑性）为人类大脑扩张的核心机制。文章确立了基因复制作为人类大脑进化的核心驱动力，为神经发育疾病的精准诊疗提供新靶点。 原文链接： https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2025.06.037 制版人： 十一 参考文献 1. Sousa, A.M.M., Meyer, K.A., Santpere, G., Gulden, F.O., and Sestan, N. (2017). Evolution of the Human Nervous System Function, Structure, and Development. Cell 170, 226–247. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2017.06.036. 2. Enard, W., Gehre, S., Hammerschmidt, K., Ho¨ lter, S.M., Blass, T., Somel,M., Bru¨ ckner, M.K., Schreiweis, C., Winter, C., Sohr, R., et al. (2009). Ahumanized version of Foxp2 affects cortico-basal ganglia circuits inmice. Cell 137, 961–971. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2009.03.041. 3. Enard, W., Przeworski, M., Fisher, S.E., Lai, C.S.L., Wiebe, V., Kitano, T.,Monaco, A.P., and Pa¨ a¨ bo, S. (2002). Molecular evolution of FOXP2, agene involved in speech and language. Nature 418, 869–872. https://doi-org.libproxy1.nus.edu.sg/10.1038/nature01025. 4. Fiddes, I.T., Lodewijk, G.A., Mooring, M., Bosworth, C.M., Ewing, A.D.,Mantalas, G.L., Novak, A.M., van den Bout, A., Bishara, A., Rosenkrantz,J.L., et al. (2018). Human-Specific NOTCH2NL Genes Affect NotchSignaling and Cortical Neurogenesis. Cell 173, 1356–1369. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2018.03.051. 5. Suzuki, I.K., Gacquer, D., Van Heurck, R., Kumar, D., Wojno, M., Bilheu,A., Herpoel, A., Lambert, N., Cheron, J., Polleux, F., et al. (2018). HumanSpecific NOTCH2NL Genes Expand Cortical Neurogenesis throughDelta/Notch Regulation. Cell 173, 1370–1384. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2018.03.067. 6. Florio, M., Heide, M., Pinson, A., Brandl, H., Albert, M., Winkler, S., Wimberger, P., Huttner, W.B., and Hiller, M. (2018). Evolution and cell-typespecificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. eLife 7, e32332. https://doi-org.libproxy1.nus.edu.sg/10.7554/eLife.32332. 学术合作组织 （*排名不分先后） 战略合作伙伴 （*排名不分先后） · 转载须知 【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。 BioArt Med Plants 人才招聘 近期直播推荐 点击主页推荐活动 关注更多最新活动！

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。 2025年8月6日，细胞药物研发企业夏同生物科技（苏州）有限公司（以下简称“夏同生物”）正式宣布完成A+轮融资，投资方为夏汇天同科技。此次融资将全力推动公司在神经脱髓鞘疾病iPSC细胞治疗领域的产品研发和临床试验进程，为神经系统疾病患者带来更具创新性的治疗方案。 此轮融资资金将主要用于推进神经脱髓鞘疾病等管线的IIT（研究者发起的临床试验）以及IND（新药临床试验申请）。 郭莹博士明确阐述了公司的发展战略：“公司将以OPC治疗髓鞘形成低下性脑白质发育不良和多发性硬化症等疾病为切入口，逐步让细胞药物在神经系统疾病领域普及，实现生物药的‘医疗普惠，共同健康’的愿景。” 公司致力于成为神经再生医学领域重编程技术应用的国际创领者，其长远目标是将干细胞转化为一种常规治疗手段，为全球数千万神经脱髓鞘疾病患者提供创新治疗方案。 技术突破与临床需求的结合，使夏同生物在资本市场备受青睐。投资方夏汇天同科技对夏同生物的技术实力和市场前景表示高度认可，期待双方未来在细胞治疗领域展开深度合作。 随着此轮融资的完成，夏同生物将加速推进其核心管线进入临床阶段。郭莹博士和她的团队肩负着“医疗普惠，共同健康”的使命，致力于让细胞药物在神经系统疾病领域普及。 关于夏同生物 夏同生物成立于 2022 年 6 月，总部位于苏州工业园区，专注于神经系统相关干细胞药物研发，尤其在神经脱髓鞘疾病治疗领域处于国际领先地位。公司由巴塞罗那大学博士郭莹（创始人兼 CEO）与中山大学深圳药学院院长邓文斌教授（联合创始人）联合创立，核心团队汇聚哈佛大学、加州大学戴维斯分校等顶尖科研机构人才，深耕神经干细胞与胶质细胞研究超 10 年。截至 2025 年，公司已完成两轮融资，拥有 iPSC 全流程技术闭环、独创 iNSC 制备技术及工业级生产能力，核心产品包括少突胶质前体细胞（OPC）、GABA 能中间神经元、神经干细胞（NSC）等，正加速推进临床试验（IIT）及新药临床试验申请（IND）。

iStock /useng Sarepta and Capricor learned of key regulatory decisions from the media and investors, and Duchenne muscular dystrophy families have turned to the news for answers. Meanwhile, the FDA insists it remains committed to notifying companies of any regulatory action before sharing information with the media or public. As Sarepta Therapeutics’ roller-coaster ride with its Duchenne muscular dystrophy gene therapy Elevidys continues to race off the tracks, patient families and clinicians are “looking at social media, they’re looking at the news constantly, trying to get an update,” according to Chet Villa, a professor in the Department of Pediatrics at Cincinnati Children’s Hospital Medical Center . Families have been left reeling, Villa told BioSpace: “It leaves people in a very challenging position where there’s a lot of new data kind of flying around.” Some of them were literally in the queue to receive their dose of Elevidys. Craig McDonald, director of the MDA Neuromuscular Disease Clinics at UC Davis, had a patient at a hotel, waiting to be treated, when the news began to break. “There were press releases going out from the FDA and from Sarepta” to provide clarification on previous information reported by an investment reporter regarding an FDA-requested hold on dosing with Elevidys for all patients. “Meanwhile, my poor patient and their family are sitting in a hotel room ready to get infused the next day,” McDonald told BioSpace . Ultimately, Sarepta agreed to pause shipment of Elevidys at close of business on July 22, so McDonald’s patient was treated just prior to the voluntary hold. “But I think that whole method of communication, with what seemed to be leaks by the FDA to the media, put our family in a very difficult and stressful position, which I don’t think is appropriate,” he said. The FDA’s public spat with Sarepta is a symptom of a larger problem, companies and patient advocates say. Capricor Therapeutics—which also works in the Duchenne muscular dystrophy (DMD) space—also found itself caught unawares when it was informed through non-official channels of the cancellation of an advisory committee meeting for its asset and then-Center for Biologics Evaluation and Research (CBER) director Vinay Prasad’s alleged plans to reject the drug. “When you run a public company, you have to be able to respond when the investors call you, and so if you don’t know first, you really are sort of put off your game,” Capricor CEO Linda Marbán told BioSpace in an interview. Sarepta Blindsided Sarepta’s problems with Elevidys began this spring, with the deaths of two teenage patients due to acute liver failure, a known complication of the AAV vectors used to deliver gene therapies. The situation escalated earlier this month when the biotech reported the death of a third patient—an adult participant in a Phase I study for SRP-9004 in limb-girdle muscular dystrophy (LGMD), which uses the same underlying technology as Elevidys. The FDA then stepped in, requesting that Sarepta pause all shipments of Elevidys. Chaos ensued. In over three decades, I’ve never seen the FDA been this engaged with investment reporters with these types of leaks without really engaging companies through appropriate channels. Craig McDonald, UC Davis When asked how he and his patients first received updates about Elevidys during the past two weeks, Villa responded: “It’s the press and social media. There’s always been a little bit of that, but the sheer volume and the seriousness of the information that’s being conveyed makes this a different time than usual.” Sarepta itself has acknowledged this reality. In a statement on July 18, in which the biotech acknowledged and refused an “informal request” from the FDA to voluntarily halt shipment of Elevidys for all DMD patients, Sarepta said it “first heard of this potential request earlier in the day at the same time the public and our patient communities did, through media reports.” “In over three decades, I’ve never seen the FDA been this engaged with investment reporters with these types of leaks without really engaging companies through appropriate channels,” McDonald said. The leaks have begun to erode the foundation of the FDA’s credibility, one analyst noted. In an investor note Tuesday addressing Prasad’s sudden departure the previous evening, BMO Capital Markets’ Kostas Biliouris wrote of the CBER’s recent “missteps” around Elevidys, “Unprecedentedly, there were multiple press leaks from the FDA, negatively impacting the confidentiality/credibility of the FDA.” It appears the leaks irked Prasad in the days leading up to his departure, too. In a letter to CBER colleagues on Saturday evening, obtained by STAT News and posted on LinkedIn by Acadia Strategy Partners principal Courtney Rice, Prasad also alluded to leaks within his department. “Some things I do find unacceptable,” he wrote, “These include surreptitiously recording meetings, screenshotting emails, and posting confidential FDA conversations on public forums/ social media or via leaking to the media.” Two days later, Prasad was gone. Capricor Caught Off Guard These recent communication issues go beyond the Sarepta saga. In June, Prasad canceled a previously scheduled advisory committee meeting for Capricor Therapeutics’ investigational cell therapy deramiocel, being developed for cardiomyopathy associated with DMD. Prasad made the decision unilaterally, according to a person familiar with the matter, STAT News reported at the time. Deramiocel was rejected early last month, with the FDA citing insufficient evidence to establish its effectiveness in a complete response letter. But on the matter of the adcomm, Marbán was caught off guard. The meeting, which had been scheduled to take place on July 30, was listed on the Federal Register—and then, ten minutes later, it wasn’t. “Investors watch these boards all day, every day, so my phone started blowing up with ‘your adcomm has been canceled. It’s been taken down. Why?’ I had no answers to give,” Marbán said. “I couldn’t make an official statement.” Capricor reached out to Prasad and other FDA offices but got “no response whatsoever,” Marbán said, until one week later, the company received a one-line email saying the adcomm had been cancelled “for now.” In addition, Capricor was contacted by a STAT reporter, Marbán said, seeking comment regarding the ouster of Nicole Verdun , the director of the FDA’s Office of Therapeutic Products, who was placed on administrative leave in June along with her deputy, Rachael Anatol. “The real issue for us was when somebody from allegedly inside the agency allegedly told this reporter that Nicole Verdun and Rachael Anatol were put on administrative leave because of an argument about our file, and that Prasad wanted to CRL us and Nicole was fighting it,” Marbán said. McDonald, who serves as lead investigator on Capricor’s HOPE-2 and HOPE-3 trials, agreed that biopharma companies should not learn about regulatory decisions through the media. “In my 30-plus years of doing clinical trials and research, I’ve never seen something like that from the FDA,” he said. In an emailed statement, an FDA spokesperson told BioSpace the agency “remains committed to our long-standing practice to notify companies of any regulatory action before sharing information with the media or the public.” Too Much Information? Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy, also expressed concern with the way in which Duchenne patient families have been receiving information regarding Elevidys. “Parents should not receive information from the press or from social media,” she told BioSpace . “They should receive it in ways that can be explained and understood.” Indeed, even in its official communications, the FDA has been unusually forthcoming with the media. In an email to BioSpace on July 18, following the revelation of the death of the LGMD trial participant, a Health and Human Services official told BioSpace the agency was “taking a hard look at pulling [Elevidys] from the market.” This type of public rumination is not new for the current HHS leadership. In April, FDA Commissioner Marty Makary raised questions when he posted on X regarding the delayed decision for Novavax’s COVID-19 vaccine: “To be clear, this is a new product that Novavax is trying to introduce to the market with a study of a different product from 2021. New products require new clinical studies.” This appeared to contradict the company’s understanding of the situation. Since taking office, Makary has proposed several policies, including a new conditional pathway for therapies for ultrarare diseases, lowering industry user fees , and the Commissioner’s Priority Voucher Program to speed drug reviews—all without many details. “The way the administration speaks in generalities about these proposals is not helpful for manufacturers who want to understand what their rights are, and observers trying to understand what the admin is doing,” Rachel Sachs, a professor of law at Washington University in St. Louis who works on health law and food and drug regulation, recently told BioSpace . Marbán agreed with this sentiment. “I was raised with the idea that actions speak louder than words, and there’s a lot of words,” she said. She pointed to a recent Squawk Box interview where Makary discussed regulatory flexibility and accelerating drug approvals, “and I think, ‘this is fantastic. This is amazing. Now let’s see it happen.”