Kearns-Sayre Syndrome

Researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. Researchers analyzed gene activity of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress. In a new study, National Institutes of Health (NIH) researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. The study, published in Frontiers in Immunology was led by researchers at the National Human Genome Research Institute (NHGRI), who analyzed gene activity of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress. "Our work is one of the first examples to study how B cells are affected in mitochondrial disease by looking at human patients," said Eliza Gordon-Lipkin, M.D., assistant research physician in NHGRI's Metabolism, Infection and Immunity Section and co-first author of the paper. Mitochondria are important components of nearly every cell in the body because they convert food and oxygen into energy. Genomic variants in more than 350 genes have been linked to mitochondrial disorders with varied symptoms depending on which cells are affected. "For children with mitochondrial disorders, infections can be life threatening or they can worsen the progression of their disorder," said Peter McGuire, M.B.B.Ch, NHGRI investigator, head of the Metabolism, Infection and Immunity Section and senior author of the study. "We wanted to understand how immune cells differ in these patients and how that influences their response to infections." Around 1 in 5,000 people worldwide have a mitochondrial disorder. Examples of mitochondrial disorders are Leigh's syndrome, which primarily affects the nervous system, and Kearns-Sayre syndrome, which primarily affects the eyes and heart. While mitochondrial disorders are known to affect organs such as the heart, liver, and brain, less is known how they affect the immune system. Using a genomic technique called single-cell RNA sequencing, which analyzes gene activity in different cell types, researchers studied immune cells found in blood. These cells include different types of white blood cells that help the body fight infections. During stressful conditions, these cells produce a microRNA called mir4485. MicroRNAs are small strings of RNA that help control when and where genes are turned on and off. mir4485 controls cellular pathways that help cells survive. "We think that B cells in these patients undergo cellular stress when they turn into plasma cells and produce antibodies, and these B cells then try to survive by producing the microRNA to cope," said Dr. McGuire. "But the B cells are too fragile due to their limited energy, so they are unable to survive the stressful conditions." Researchers used a technique called VirScan to look at all past viral infections, assess how well the immune system fought those infections and see the effects of B cells and plasma cells on antibody production. With a weaker antibody response, the immune systems in children with mitochondrial disorders are less able to recognize and neutralize invading viruses and clear infections. Researchers aim to use the results of this study to guide future treatment of patients with mitochondrial disorders, noting that more translational studies are needed in this research area.

Transmition Electron microscopy of an epithelial cell showing mitochondria/courtesy of Dlumen/iStock They’re the powerhouses of the cell, generating energy for nearly every organ in the body. But when mitochondria are dysfunctional, the resulting power outage can cause devastation for children and adults with rare and ultra-rare diseases. One rare mitochondrial disease, Friedreich’s ataxia, saw its first approval in March when the FDA greenlit Reata Pharmaceuticals’ Skyclarys for adults and adolescents 16 and older. While this bodes well for adult diseases, there have not been many recent advances in treating pediatric mitochondrial diseases, said Jan Smeitink, CEO of Khondrion, a company developing symptomatic treatments for mitochondrial diseases. “The good thing is that, at least now, there is this huge interest in primary mitochondrial diseases, so more companies are working in the space,” he told BioSpace. “It’s also good to notice that different companies have compounds working on different targets.” Jan Smeitink A Glimmer of Hope in Pearson Syndrome One of these companies is Israel-based Minovia Therapeutics, which is developing a mitochondrial cell therapy for Pearson syndrome, a multisystem disease caused by single, large deletions in mitochondrial DNA (mtDNA). The mitochondria are the only place in the cell where there is DNA outside of the nucleus, Natalie Yivgi-Ohana, co-founder and CEO of Minovia, told BioSpace. This makes the organelle particularly vulnerable. “It’s exposed. It’s circular. It has no protections, no proofreading, so mutations just accumulate with time.” Pearson syndrome affects fewer than 1,000 people in the U.S., according to the Genetic and Rare Diseases Information Center. “Almost 50% of [patients] will die before the age of five, and the rest will just develop a multisystemic, terrible disease that affects almost every organ system,” Yivgi-Ohana elaborated. Patients experience neurodegeneration, muscular dysfunction, cardiac dysfunction and diabetes. “It’s almost like the whole body is collapsing.” Minovia’s Mitochondrial Augmentation Technology (MAT) platform involves extracting a patient’s hematopoietic stem cells, enriching them with healthy mitochondria from a donor and then infusing them back into the body. This allows the cell’s natural processes to select for the healthy versions of the organelles, Yivgi-Ohana said. Pearson syndrome is the only mitochondrial disease where bone marrow failure occurs, so “hematopoietic stem cells are very relevant to treat at least the hematopoietic environment of that patient,” Yivgi-Ohana said. Generally, mitochondria—and consequently­—mtDNA, is inherited only from the mother. But Pearson is usually caused by de novo mutations, enabling the mother to serve as a donor, she said. Natalie Yivgi-Ohana In a compassionate use study, seven young patients—four with Pearson syndrome and two with another primary mitochondrial disease, Kearns-Sayre syndrome (KSS)—were treated with MAT (MNV-101). Prior to treatment, all patients had potentially life-threatening symptoms, including advanced multi-organ disease, according to Minovia. Minovia extracted one unit of blood from the donor, isolated the mitochondria from the white blood cells and introduced them into the patient’s hematopoietic stem cells in the lab before re-injecting those into the patient. Treatment with MNV-101 was well-tolerated and resulted in normal mitochondrial DNA in the blood of four patients, which Minovia said indicated a reduction of mitochondria containing the disease-causing deletions. “The first few patients showed remarkable improvement and reversal of the disease,” Yivgi-Ohana said. She shared the story of a six-and-a-half-year-old boy who was confined to a baby stroller due to stunted growth, muscle weakness and fatigue. After treatment with MAT, “the first thing that we observed in this patient was a burst of energy in the waking hours of the day,” Yivgi-Ohana said. The baby stroller disappeared and the child started to walk and run. The boy continued to improve, and his kidney function stabilized for four years after treatment before beginning to deteriorate in the past two years, Yivgi-Ohana said. Based on this patient and eleven others who have been treated with MAT, she believes another dose of MNV-101 will be required. Leigh Syndrome and MELAS Spectrum Disorders Waltham, Mass.–based IMEL Biotherapeutics aims to restore mitochondrial function with cell-based therapies to treat both genetic and age-related diseases. On the genetic side, IMEL is targeting Leigh syndrome, a severe neurometabolic disorder that affects children carrying certain mutations in their mtDNA. The company’s Mitochondrial Replaced Cells (MirC) technology allows it to deplete the dysfunctional mitochondria and replace them with healthy mitochondria, Silvia Noiman, founder, chair and CEO of IMEL, told BioSpace. Silvia Noiman IMEL is currently testing the MirC process in animal models resembling Leigh syndrome. Using the MirC process in stem cells and T cells from both animal models and healthy humans, IMEL has shown that it can replace almost 90% of the host cells’ dysfunctional mitochondria with functional organelles, Noiman said. She believes the technology “can be a game changer.” Noiman will expound on the age-related impacts of mitochondrial disorders at the Biomed Israel Conference, held this week in Tel Aviv. Mitochondrial disorders affect adults too. Khondrion has several therapies in development for these diseases. Its most advanced product is sonlicromanol for the treatment of cognitive dysfunction in adults with MELAS spectrum disorders. Classical MELAS spectrum disorders, including maternally inherited diabetes and deafness (MIDD) and mixed phenotypes, are most often caused by a mutation in the MT-TL1 gene in the mtDNA. The most oft-affected organs are the brain, muscles and pancreas, Smeitink said. Between Phase IIb and open-label extension studies, Smeitink said the company has good safety data for up to 78 weeks. Khondrion is currently discussing Phase III trial design with the FDA and European Medicines Agency. Sonlicromanol, a reductive and oxidative distress modulator with anti-inflammatory properties, aims to correct the outward manifestations of mutations in the cell lines of patients with mitochondrial diseases. Khondrion is also testing the drug for the treatment of mitochondria-based movement disorders in children. The Path Forward The mitochondrial disease space comprises approximately 300 neuro-metabolic genetic disorders, according to Khondrion. “The problem with mitochondrial diseases is that it’s not one disease. It’s hundreds and hundreds of diseases,” Mary Kay Koenig, pediatric neurologist and director of the Mitochondrial Center of Excellence at UTHealth Houston, told BioSpace. Gene replacement therapies and DNA modifications are focused on a very small proportion of the diseases, she said. For Smeitink, small molecule therapies are “the way to go” in treating mitochondrial diseases, at least for the next 10 years. He said gene and cell therapy also hold promise but “need a little bit more time as several obstacles first have to be overcome.” He pointed to vector design, targeted tissue tropism and efficient delivery, transgene expression and immunotoxicity. Yivgi-Ohana said that autologous hematopoietic stem cells are the most trusted cell therapy. She said that the riskiest part of such treatment is typically the preconditioning—clearing the bone marrow with chemotherapy to allow engraftment of cells in the bone marrow niche—but added that this is not done for Pearson patients because their bone marrow has low cellular content, meaning there is space in the bone marrow niche for engraftment of the augmented cells. Another primary challenge is phenotyping, Koenig said. “You can’t really find a treatment for something if you don’t understand what the natural history of it is, and I think . . . we’re still in the process of trying to understand [mitochondrial] diseases,” she said. “It makes it really hard to determine whether or not a drug is efficacious if you don’t know what’s supposed to happen to the patient” in the natural course of the disease. One initiative, The Leigh Syndrome Roadmap Project: A Natural History Study, is trying to address this challenge. The project, being run out of the Children’s Hospital of Philadelphia, aims to better understand the natural history of Leigh syndrome and determine proper endpoints for clinical trials, Koenig said. Currently, there are not many ongoing studies in mitochondrial diseases for children, Smeitink noted. While there are around 200 active trials for mitochondrial diseases listed on ClinicalTrials.gov as of May 2023, just 10 of these are for Leigh’s syndrome and two are for Pearson syndrome. “That is unfortunate,” he said. “But it will change, I’m sure.” Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn: and Twitter: @chicat08. The Biomed Israel conference paid for Heather McKenzie to travel to Israel to meet with Minovia Therapeutics in December 2022.

▎药明康德内容团队编辑在地球远古时期的某一刻，两个独立的单细胞生命形式——一个古核生物和一个细菌，以共生或奴役方式合二为一。在接下来的20多亿年里，这种细菌进化成为线粒体，它仿佛是细胞中的“发电厂”，通过“燃烧”葡萄糖等碳源，产生化学能量以供细胞生命活动所需。不仅如此，它们还能代谢胆固醇，合成激素和神经递质。可以说，线粒体这个“细胞发电厂”是我们能够走上楼梯、长跑、跳跃和游泳、欢笑和爱的原因。没有它们，人类无法进化为高级生命体，我们仍然会和无数真菌细菌一般，在泥沼里黏糊糊地活着。图片来源：123RF这就是为什么当线粒体出问题时，其后果往往是灾难性的。形式多样的线粒体疾病中，一种致病方式是线粒体DNA序列的大段片段自发消失，由此造成线粒体DNA缺失综合征（SLSMDs）。这是一系列累及多个器官组织的严重疾病，通常在儿童十岁后开始显现症状，表现为渐进性的多系统衰竭，症状包括听力和视力丧失、肌肉无力、胃肠道和心脏问题、痴呆和早夭。目前线粒体DNA缺失综合征没有任何治疗方法，但人们并不甘心就此认输。在过去的七年里，以色列的医生和科学家一直在研究一种潜在的治疗方法，通过向患者的造血干细胞中引入由患者母亲捐赠的健康线粒体，来增加这些细胞内的线粒体DNA含量。造血干细胞可以产生不同类型的血细胞，经改造后有望改善全身多个器官系统的病变。现在，这种创新治疗方式已步入临床研究阶段，在六名SLSMDs儿童患者身上进行了尝试。试验结果证明了这项疗法的安全性，并且参加试验的患儿都显示出症状改善的迹象。不久前，《科学》杂志的子刊Science Translational Medicine报告了这一疗法的相关临床试验结果。这种治疗方法，研究人员将其命名为“线粒体增强术（mitochondrial augmentation therapy，MAT）”，它让6名小患者的生活质量得到了显著的提高。领导这项研究的第一作者、以色列Sheba医学中心（Sheba Medical Center）的血液学家Elad Jacoby博士回忆道：“与他们的同龄人相比，这些孩子非常虚弱。一个6岁的男孩只能坐在婴儿车里在医院行动，另一个女孩则卧床不起。治疗后几周，她便获得了站立的能力。男孩也开始跑来跑去，并且能够保持足够长的清醒时间，吃得更多，体重也增加了。”▲研究的第一作者Elad Jacoby博士（图片来源：以色列Sheba医学中心官网）如果在未来的临床试验中这些结果获得重复，MAT疗法有望成为一种新的治疗选择，不仅可以治疗这种罕见的遗传疾病，还可以治疗一系列由线粒体损伤引起的疾病和机体损伤。其他学者也对这项研究给予了高度评价。波士顿儿童医院的心脏外科医生、哈佛大学医学院研究员、线粒体疗法研发公司Cellvie的联合创始人James McCully博士说道：“这是一项很好的研究，表明线粒体移植在这些罹患线粒体基因缺失疾病的患者中是安全的。”虽然没有参与这项研究，但他表示“很高兴看到有人在做这项工作，这表明整个领域正在向前发展。”值得一提的是，McCully博士的团队在线粒体移植领域深耕多年，他们的工作为MAT疗法的诞生提供了宝贵的研究基础。▲James McCully博士（图片来源：Cellvie公司官网）细胞中的“发电厂”2009年，McCully博士领导的团队首次从动物实验中找到了证据，证明线粒体移植可以帮助心脏从损伤中恢复。几十年来，他一直在观察当患者的心脏血液供应被切断时，这些患者会发生什么。心脏缺氧造成的伤害似乎是无法逆转的——无论他和其他外科医生做任何尝试来保护患者，缺氧组织中的线粒体仍旧被损坏得无法修复，即使在血液供应恢复后，这些心脏也没能完全恢复过来。有一天，McCully博士突发奇想，如果把身体其他地方的健康线粒体注入一个受损的心脏，会发生什么？他们在一头猪身上进行了尝试，几分钟后，它的心脏就恢复了力量，并且跳动得更快，推动更多的血液通过它的身体。当McCully博士的团队发表这一结果时，许多科学家不相信线粒体可以进入新的细胞并加入其能量供应链，但这项研究却深深触动了Natalie Yivgi-Ohana博士，她开始寻找投资者，以创立一家专注于开发线粒体疗法的新公司。2012年，在她与其他合作者的努力下，Minovia公司成立了，这家公司正是此次研究所用到的MAT治疗技术的开发者。▲Minovia公司首席执行官兼联合创始人Natalie Yivgi-Ohana博士（图片来源：Minovia公司官网）从辅助生殖技术到遗传病良方——“三亲试管婴儿”的启示Natalie Yivgi-Ohana博士对于线粒体疗法的信心并不是凭空产生的，她曾接受过胚胎学家的培训，深刻地认识到“三亲试管婴儿”技术在预防线粒体疾病方面的巨大前景。众所周知，我们的生命源自精子和卵子的结合所产生的受精卵，而受精卵中的遗传物质不仅只有精子和卵子细胞核中的染色体，位于卵子细胞质中的线粒体所携带的DNA对于胚胎发育和后续生命活动而言同样至关重要。不同于染色体，线粒体中的DNA只来源于母亲，一旦母亲卵子中的线粒体DNA发生突变或缺失时，这种线粒体基因的缺陷便会遗传给所有的下一代，导致这位母亲的孩子都患上线粒体疾病。所谓“三亲试管婴儿”，是通过将母亲卵子中取出的细胞核移植到捐赠者的卵子中（已移除细胞核），用捐赠者卵子中的健康线粒体取代母亲卵子中的缺陷线粒体，之后再与父亲的精子结合完成受精。如此一来，新生儿的体内便有了三个人的遗传信息——除了父母之外，还有一位匿名捐赠者的线粒体DNA。来自纽约新希望生殖中心（New Hope Fertility Center）的医生张进（John Zhang）完成了这一壮举，世界首例“三亲试管婴儿”在2016年诞生。▲世界首例“三亲试管婴儿”和张进博士（图片来源：参考资料[5]）“三亲试管婴儿”的成功问世证明了线粒体替代疗法的可行性，Yivgi-Ohana博士的团队决定把线粒体治疗引入遗传病的领域。最初，Minovia公司计划将线粒体直接注入Leber遗传性视神经病变的患者眼睛中来进行概念验证，但在2016年，一个患有皮尔逊综合征（Pearson syndrome）的小男孩的家庭找到了Yivgi-Ohana博士，这使她改变了心意，将首次试验的对象改为皮尔逊综合征患者。皮尔逊综合征是一种极其罕见的线粒体缺失综合征，全世界只有不到100人患病。这种疾病发病较早，通常是在患者出生后的第一年发病，并且会导致严重的骨髓衰竭，患者需要经常输血。由于造成该疾病的线粒体DNA缺失是自发产生的，这类患者的母亲并不携带这种突变，使得患者母亲可以作为线粒体捐赠者。之后，Minovia公司与这名小患者接受治疗的医疗机构——专门治疗皮尔逊综合征和其他线粒体疾病的Sheba医学中心接洽，商讨开展一项临床试验，该试验在2019年中期开始招募患者。与此同时，该公司与Jacoby博士和Sheba医疗团队的其他成员合作，尝试在同情用药计划（compassionate use program）下使用这种实验性疗法来治疗这名男孩。MAT治疗，来自妈妈生命的馈赠2017年，医生从这名男孩的骨髓和他母亲的血液中收集了造血干细胞。他们从母亲的细胞中分离出了线粒体，然后诱导男孩的造血干细胞通过胞饮作用将母亲的线粒体摄入细胞内。最后，这些被赋予额外线粒体的细胞被输回孩子体内。紧接在这名孩子之后，又有五个患有线粒体DNA缺失综合征的孩子接受了这种治疗，其中三名孩子患有皮尔逊综合征，另外两名患有Kearns-Sayre综合征。▲MAT疗法操作流程（图片来源：参考资料[6]）血细胞的准备和移植工作由Sheba医学中心的医疗团队负责，与一般的造血干细胞移植过程略有不同，他们决定跳过清髓性预处理（conditioning）过程，这个过程需要清除患者体内的异常造血干细胞，为改造后的造血干细胞移植让路，但考虑到这些患儿的身体状况，这个步骤的风险太大，最终被省去。由于该治疗方案略去了清髓过程，并且所植入的线粒体来源于患者自己的母亲，研究人员难以追踪线粒体增殖的效果如何。于是研究人员测量了正常线粒体DNA与缺失的线粒体DNA的比例、线粒体DNA分子的总数，以及细胞产生能量的能力作为衡量治疗后线粒体功能的替代指标，这些指标在移植后均增加。试验数据让研究人员乐观地认为，捐赠者的线粒体在患者体内存活了下来，并在新的细胞中作出贡献。前路漫漫，未来可期MAT疗法的1/2期临床试验在2019年6月正式启动，试验结果预计将在明年公布。对此，Jacoby博士表示：“我想我们已经认识到，用新的思路来解决罕见病是可行的，但在这个过程中，与其说我们找到解决问题的答案，更应该说我们发现了更多尚待解决的问题。”Natalie Yivgi-Ohana博士也认为，这一领域仍有许多亟待解决的问题需要进一步研究，比如患者是否需要多次治疗？尽管患者在治疗后立即有了改善，但一年后，其中一些变化开始减弱。移植前的预处理能否使治疗更加有效？此外，对于现货型治疗产品，将需要何种程度的捐赠者匹配度？想到这些问题，Yivgi-Ohana博士说道：“这是一个令人兴奋的时刻，但它仍然只是一个开始。”Minovia公司计划今年在皮尔逊综合征患者中开始一项基于现货型MAT疗法的试验，这种现货型治疗产品同样由造血干细胞制作而成，其细胞内所富集的线粒体取材自捐赠者胎盘。对于Minovia公司在MAT疗法领域的未来布局，James McCully博士十分看好，他认为，如果能将这一项目推进到更大的研究中并纳入更多的患者，那将是一个巨大飞跃。除了MAT治疗领域的进展，线粒体移植疗法近年的发展势头也十分迅猛，McCully博士的团队目前正在与美国FDA讨论，以尝试启动他们自己的关键性试验，来测试线粒体移植如何帮助心脏移植患者在手术后的恢复。2021年，他的团队发表了线粒体移植在一组患有先天性心脏缺陷的婴儿身上的首次临床应用结果，这项小型试点研究发现，线粒体被注入冠状动脉后，迅速被受损的心脏细胞吸收，并在那里促进能量生产和其他代谢功能。根据回顾性数据，这种治疗的临床益处非常显著——80%接受治疗的患者能够脱离呼吸辅助机，而接受标准治疗的患者中这一比例仅为30%。“线粒体疗法真的很强大”，McCully博士感叹道，“我们已经观察到它在心脏、肺部、肌肉中发挥作用，我认为它的潜力是无限的。”作为药明康德旗下专注于细胞和基因疗法的CTDMO，药明生基致力于加速和变革基因和细胞治疗及其他高端治疗的开发、测试、生产和商业化。药明生基能够助力全球客户将更多创新疗法早日推向市场，造福病患。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] In a first, children with rare genetic diseases get mitochondrial transplants from their mothers，Retrieved Jan 29th, 2023, from https://www.statnews.com/2022/12/21/children-with-rare-genetic-disease-get-mitochondrial-transplant-from-mothers/[2] Jacoby, Elad et al. “Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.” Science translational medicine vol. 14,676 (2022): eabo3724. doi:10.1126/scitranslmed.abo3724[3] Minovia Therapeutics Reports First Clinical Data Demonstrating Disease-Modifying Efficacy and Safety of Mitochondrial Augmentation Therapy in Pediatric Patients with Primary Mitochondrial Diseases，Retrieved Jan 29th, 2023, from https://www.globenewswire.com/news-release/2022/12/21/2578165/0/en/Minovia-Therapeutics-Reports-First-Clinical-Data-Demonstrating-Disease-Modifying-Efficacy-and-Safety-of-Mitochondrial-Augmentation-Therapy-in-Pediatric-Patients-with-Primary-Mitoch.html#:~:text=%E2%80%9CThese%20findings%20demonstrate%20that%20mitochondrial%20augmentation%20therapy%20is,M.D.%2C%20Ph.D.%2C%20Hemato-oncology%20Pediatric%20department%2C%20Sheba%20Medical%20Center.[4] Mitochondrial DNA Deletion Syndromes，Retrieved Jan 29th, 2023, from https://www.chop.edu/conditions-diseases/mitochondrial-dna-deletion-syndromes[5] Reardon, S. ‘Three-parent baby’ claim raises hopes — and ethical concerns. Nature (2016). https://doi.org/10.1038/nature.2016.20698[6] Mitochondrial Augmentation Technology (MAT)，Retrieved Jan 29th, 2023, from https://minoviatx.com/therapy/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