PAPD7

在一项新的研究中，来自美国华盛顿大学和科罗拉多大学等研究机构的研究人员确定了一种潜在的治疗策略，用于治疗一种罕见的骨髓衰竭综合征。 骨髓是骨骼内的海绵状组织，负责制造红细胞、白细胞和血小板。骨髓衰竭综合征会导致患危险性感染、贫血和血癌风险的增加。 在一项新的研究中，来自美国华盛顿大学和科罗拉多大学等研究机构的研究人员确定了一种潜在的治疗策略，用于治疗一种罕见的骨髓衰竭综合征，即皮肤异色病合并中性粒细胞减少症（poikiloderma with neutropenia, PN）。这项新的研究也可能对治疗其他具有类似潜在功能障碍的骨髓衰竭综合征产生影响。相关研究结果发表在2023年3月3日的Science期刊上，论文标题为“USB1 is a miRNA deadenylase that regulates hematopoietic development”。 PN是由一个叫做USB1的基因的突变引起的。尽管知道了导致该疾病的遗传错误，但该错误导致骨髓衰竭的具体细节长期以来一直是个谜。当骨髓衰竭时，身体不能制造健康的红细胞、白细胞和血小板。患有这类疾病的人遭受感染的风险增加，容易患上皮肤癌和血癌。 论文共同通讯作者、华盛顿大学圣路易斯医学院医学副教授Luis Batista博士说，“对于PN而言，目前没有治愈方法。患者面临着因感染并发症而死亡的高风险，科学家们不知道为什么这个基因的突变会导致骨髓衰竭。在这项新的研究中，我们发现了一种酶的新作用，为未来的临床试验打开了大门。有一些正在研究的药物可以阻断这种酶，所以我们希望治疗这些患者的临床医生可能会发现这是一个有前途的策略。” 这些作者研究了为模拟PN而设计的人类胚胎干细胞，发现microRNA分子的加工存在问题。这种加工问题导致特定的microRNA分子比正常情况下降解得更快。如果没有足够水平的这些microRNA，这些干细胞就不能产生正常的血细胞。 论文共同第一作者、Batista实验室博士后研究助理Hochang Jeong博士说，“我们的研究显示，正常的USB1作为一种microRNA去腺苷化酶，切除这些microRNA的长尾巴，这稳定了它们的结构，使它们有时间完成形成血液产品的工作。当USB1在这种疾病中发生突变时，这些microRNA的尾巴比正常情况下更长。我们知道，拥有较长的尾巴会使microRNA和其他类别的RNA分子更容易成为降解的目标。我们了解到的情况是，在加长microRNA尾巴的酶和切除microRNA尾巴的酶之间应该有一个平衡。” 虽然目前还没有一种已知的方法来恢复正确切除microRNA尾巴的能力，但已经有研究性药物可以阻断负责切除microRNA尾巴的酶。在这种疾病中阻断这种酶可能会恢复microRNA尾巴的增加和减少之间的平衡。 负责添加microRNA尾巴的酶被称为PAPD5和PAPD7，这些酶的抑制剂已经在包括乙型肝炎在内的其他疾病的人类临床试验中进行了研究。防止microRNA长尾巴的加入稳定了microRNA的结构，增加了它们的水平，并恢复了这些干细胞的正常血细胞形成。这些作者正在与行业伙伴合作，开发新的PAPD5和PAPD7抑制剂，专门用于治疗这种疾病和类似的疾病。 Batista说，“我们正在与不同的公司合作，开发更好和更特异性的PAPD5抑制剂来治疗这种罕见的骨髓衰竭综合征。在我的实验室里，我们是罕见疾病研究的大力倡导者。综合来看，罕见病一点都不罕见，这些患者值得我们关注。抑制PAPD5有望成为其他骨髓衰竭综合征的潜在治疗方法。”（生物谷 Bioon.com） 参考资料： Ho-Chang Jeong et al. USB1 is a miRNA deadenylase that regulates hematopoietic development. Science, 2023, doi:10.1126/science.abj8379. 内容来源于网络，如有侵权，请联系删除。

▎药明康德内容团队编辑说到攻克疾病，比起从零开始开发新疗法，重新挖掘现有药物的潜力，“老药新用”治疗目前无法被治愈的疾病或许更加能给人意外之喜。最近，来自华盛顿大学和科罗拉多大学的科学家们便在探究一种罕见性骨髓衰竭综合征时收获了这种惊喜，他们不仅揭示了这种疾病背后的病理机制，而且还发现一种曾经在临床试验中研究过的药物可以通过阻断一种关键酶来逆转这种缺陷。这篇研究近期以长文的形式发表在顶级学术期刊《科学》上。骨髓是骨骼内负责生成红细胞、白细胞和血小板的组织，如果骨髓发生病变，可能导致患者的造血能力异常，从而引发感染、贫血，甚至发展为癌症。而有这样的一群患者，由于先天性的基因突变不得不面对这些风险，他们便是皮肤异色病合并中性粒细胞减少症（PN）患者，目前临床上针对这种罕见病并没有治愈的方法。PN是由USB1基因突变引起的罕见病。早在1991年，医生们便在纳瓦霍族土著儿童中发现了一种罕见的综合征，这些患儿的胳膊和腿上出现了一种凸起的红色皮疹，呈圆形扩散，并随后出现色素沉着变化和皮肤表面可见的扩张血管。除了皮疹，患者还出现了白细胞减少，这使得他们容易受到致命感染，罹患皮肤癌和血癌的风险也更高。尽管科学家们已经知悉导致这种疾病的病症及其致病基因突变，但这种突变是如何导致骨髓衰竭的具体机制一直是个谜。现在，科学家们宣布已经破解了这个谜团，并找到了一种潜在的治疗药物。图片来源：123RF在这篇研究中，研究人员使用CRISPR-Cas9基因编辑技术在人类胚胎干细胞中制造了USB1基因突变。他们发现带有突变的干细胞外观和行为正常，便继续刺激它们转化为造血祖细胞。起初，USB1突变型细胞和对照细胞都按预期分化。但是在实验第16天后，研究小组注意到突变细胞中祖细胞的转化已经下降。经过一系列细胞实验和RNA测序分析后，研究人员揭示了其中的奥秘——血细胞分化所需的关键microRNA分子序列已经提前被破坏，没有足够水平的microRNA分子，干细胞就不能发育成正常的血细胞。图片来源：123RF在正常情况下，USB1基因编码的蛋白通过去除microRNA的分子的“尾巴”来稳定其结构。microRNA分子的尾巴也是一串核苷酸序列，这种序列传递给细胞的信号指示该microRNA分子应该被破坏。正如研究第一作者Ho-Chang Jeong博士的解释，USB1基因编码的“去尾”酶给了microRNA分子足够的时间来发挥它的作用。当它完成使命时，“加尾”酶PAPD5或PAPD7再将这种“尾巴”结构放回原处。但是当USB1基因发生突变，在没有这种“去尾”酶的情况下，microRNA分子在帮助祖细胞分化成血细胞之前就被破坏了，这会导致骨髓衰竭和随之而来的并发症。科学家们想要重新恢复“去尾”酶和“加尾”酶之间的平衡，并保护microRNA分子免于被破坏。虽然目前还没有已知的方法来恢复USB1突变细胞正确去除尾巴的能力，但已经有在研药物可以抑制为microRNA分子加上“尾巴”的酶活性。研究人员设想，在PN中阻断这种“加尾”酶可能会恢复平衡。于是他们测试了PAPD5抑制剂RG7834（也称为RO7020322）是否能有预期的效果。罗氏曾在临床试验中用这种药物治疗乙型肝炎，但最终罗氏放弃了该药物的开发。图片来源：123RF研究人员用RG7834处理了UB1突变型细胞，并研究它如何影响microRNA分子“尾巴”的添加。在施加这种药物后，研究人员观察到了细胞中无尾microRNA分子数量的增加，表明它有效遏制了microRNA分子的“加尾”过程、保护了这些分子免于被破坏。随后，研究人员继续评估了它是否也能恢复血细胞分化，而事实并没有让他们失望。经过RG7834的治疗后，突变型细胞中的中性粒细胞形成被显著改善，这表明RG7834有望成为PN的潜在治疗策略。最后，研究人员在USB1突变细胞中直接上调了microRNA水平，结果正如他们的预计——逆转microRNA水平后，血细胞的形成也被恢复，这进一步验证了他们的发现，通过抑制参与microRNA分子“加尾”作用的酶活性，可以逆转因USB1突变造成的血细胞异常，其作用等效于恢复被破坏的microRNA水平。据了解，主导该研究的科学家们现在正与业界合作伙伴合作，将他们的发现推向下一阶段。他们希望，这些发现不仅能为PN带来新的治疗方法，还能为其他拥有类似致病机制的骨髓综合征带来新的治疗方法。药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲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] Jeong, Ho-Chang et al. “USB1 is a miRNA deadenylase that regulates hematopoietic development.” Science (New York, N.Y.) vol. 379,6635 (2023): 901-907. doi:10.1126/science.abj8379[2] Possible treatment strategy identified for bone marrow failure syndrome，Retrieved March 7th, 2023 from https://medicine.wustl.edu/news/possible-treatment-strategy-identified-for-bone-marrow-failure-syndrome/[3] Drug once tested for hep b could help rare bone marrow syndrome，Retrieved March 7th, 2023 from https://www.fiercebiotech.com/research/drug-once-tested-hepatitis-b-could-help-patients-rare-bone-marrow-syndrome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

Scientists discovered that hepatitis A viral replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases, and they used a molecule to stop replication at a key step, making it impossible for the virus to infect liver cells. The viral replication cycle is crucial for a virus to spread inside the body and cause disease. Focusing on that cycle in the hepatitis A virus (HAV), UNC School of Medicine scientists discovered that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases. They also found that the oral compound RG7834 stopped replication at a key step, making it impossible for the virus to infect liver cells. These findings, published in the Proceedings of the National Academy of Sciences, are the first to demonstrate an effective drug treatment against HAV in an animal model of the disease. "Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof-of-principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings," said senior author Stanley M. Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, and member of the UNC Institute for Global Health and Infectious Diseases. Lemon, who in the 1970s and 80s was part of a Walter Reed Army Medical Center research team that developed the first inactivated HAV vaccine administered to humans, said research on HAV tapered off after the vaccine became widely available in the mid-1990s. Cases plummeted in the 2000s as vaccination rates skyrocketed. Researchers turned their attention to hepatitis B and C viruses, both of which are very different from HAV and cause chronic disease. "It's like comparing apples to turnips," Lemon said. "The only similarity is that they all cause inflammation of the liver." HAV is not even part of the same virus family as hepatitis B and C viruses. Hepatitis A outbreaks have been on the rise since 2016, even though the HAV vaccine is very effective. Not everyone gets vaccinated, Lemon pointed out, and HAV can exist for long periods of time in the environment -- such as on our hands and in food and water -- resulting in more than 44,000 cases, 27,000 hospitalizations and 400 deaths in the United States since 2016, according to the CDC. Several outbreaks have occurred over the past several years, including in San Diego in 2017 driven largely by homelessness and illicit drug use, causing severe illness in about 600 people and killing 20. In 2022, there was a small outbreak linked to organic strawberries in multiple states, leading to about a dozen hospitalizations. Another outbreak in 2019 was linked to fresh blackberries. Globally, tens of millions of HAV infections occur each year. Symptoms include fever, abdominal pain, jaundice, nausea, and loss of appetite and sense of taste. Once sick, there is no treatment. In 2013, Lemon and colleagues discovered that the hepatitis A virus changes dramatically inside the human liver. The virus hijacks bits of cell membrane as it leaves liver cells, cloaking itself from antibodies that would have otherwise quarantined the virus before it spread widely through the blood stream. This work was published in Nature and provided insight into how much researchers had yet to learn about this virus that was discovered 50 years ago and has likely caused disease dating back to ancient times. A few years ago, researchers found that hepatitis B virus required TENT4A/B for its replication. Meanwhile, Lemon's lab led experiments to search for human proteins that HAV needs in order to replicate, and they found ZCCHC14 -- a particular protein that interacts with zinc and binds to RNA. "This was the tipping point for this current study," Lemon said. "We found ZCCHC14 binds very specifically to a certain part of HAV's RNA, the molecule that contains the virus's genetic information. And as a result of that binding, the virus is able to recruit TENT4 from the human cell." In normal human biology, TENT4 is part of an RNA-modification process during cell growth. Essentially, HAV hijacks TENT4 and uses it to replicate its own genome. This work suggested that stopping TENT4 recruitment could stop viral replication and limit disease. Lemon's lab then tested the compound RG7834, which had previously been shown to actively block Hepatitis B virus by targeting TENT4. In the PNAS paper, the researchers detailed the precise effects of oral RG7834 on HAV in liver and feces and how the virus's ability to cause liver injury is dramatically diminished in mice that had been genetically modified to develop HAV infection and disease. The research suggests the compound was safe at the dose used in this research and the acute timeframe of the study. "This compound is a long way from human use," Lemon said, "But it points the path to an effective way to treat a disease for which we have no treatment at all." The pharmaceutical company Hoffmann-La Roche developed RG7834 for use against chronic hepatitis B infections and tested it in humans in a phase 1 trial, but animal studies suggested it may be too toxic for use over long periods of time. "The treatment for Hepatitis A would be short term," Lemon said, "and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects." This research was a collaboration between the Lemon lab and the lab of Jason Whitmire, professor of genetics at the UNC School of Medicine. Lemon and Whitmire are members of the UNC Lineberger Comprehensive Cancer Center. First authors of the PNAS paper are You Li and Ichiro Misumi. Other authors, all at UNC, are Tomoyuki Shiota, Lu Sun, Erik Lenarcic, Hyejeong Kim, Takayoshi Shirasaki, Adriana Hertel-Wulff, Taylor Tibbs, Joseph Mitchell, Kevin McKnight, Craig Cameron, Nathaniel Moorman, David McGivern, John Cullen, Jason K. Whitmire, and Stanley M. Lemon. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R01-AI131685), (R01-AI103083), (R01-AI150095), (R21-AI163606), (R01-AI143894), (R01-AI138337). The UNC Pathology Services Core and UNC High-Throughput Sequencing Facility were supported in part by a National Cancer Institute Center Core Support Grant (P30CA016086) to the UNC Lineberger Comprehensive Cancer Center.