Spastic Paraplegia, Hereditary

引言肥厚性心肌病是一种常见的遗传性心肌病。尽管HCM已被报道与许多参与肌体蛋白生物力学的基因变异相关，但在部分HCM患者中尚未发现致病基因。FARS2 (线粒体phenylalanyl-tRNA合成酶)是线粒体氨基酰基-tRNA合成酶的一种，在线粒体翻译机制中起作用。FARS2的几种变体已被认为可引起神经系统疾病；然而，涉及其他器官的FARS2相关疾病尚未报道。2024年2月16日，空军军医大学吴元明、刘丽文、Chen Kun共同通讯在Circulation（IF 38）在线发表题为“FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System”的研究论文，该研究表明FARS2缺乏通过破坏线粒体稳态和线粒体质量控制系统引起心肌病。该研究在HCM患者中发现了7个未报道的FARS2变异。心脏特异性Fars2缺陷小鼠表现为心脏肥厚、左心室扩张、进行性心力衰竭伴心肌和线粒体功能障碍、寿命短。杂合子心脏特异性Fars2R415L小鼠在4周龄时表现出心肌肥厚的倾向，并伴有心肌功能障碍。此外，Fars2敲低的斑马鱼出现心包水肿和心力衰竭。FARS2缺陷通过直接阻断mt-tRNAPhe的氨基酰化和抑制线粒体蛋白的合成来破坏线粒体稳态，最终通过加速线粒体超片段化和破坏线粒体相关的自噬，导致线粒体质量控制系统失衡。使用腺相关病毒9或特异性抑制剂干扰线粒体质量控制系统，通过恢复线粒体稳态，减轻由FARS2缺陷引发的心脏和线粒体功能障碍。该研究揭示了先前未被认识到的FARS2在心脏和线粒体稳态中的作用，为遗传性心肌病的分子诊断和预防以及FARS2相关心肌病的治疗选择提供新的见解。肥厚性心肌病(HCM)是最常见的遗传性心肌病，发病率约为1/500。HCM以左心室不对称增厚和舒张功能受损为特征，是心力衰竭(HF)和心源性猝死的主要原因在过去的20年里，分子遗传学的进展已经揭示了超过1000个与HCM相关的遗传变异，其中大多数与肌体基因有关，如MYH7和MYBPC3。然而，相当比例的HCM患者没有表现出任何已知遗传变异的证据。因此，其他新的致病变异可能负责或促成这些患者的HCM表型。线粒体独立于细胞质，具有由线粒体DNA (mtDNA)编码的tRNA、核糖体RNA和核DNA编码的线粒体氨基酰基tRNA合成酶(mtARS)调节的翻译机制。超过1500个线粒体蛋白中只有13个是在线粒体中合成的。这13种蛋白构成了OXPHOS复合物的关键亚基，mtARS负责线粒体蛋白的合成，其中涉及到tRNA与其同源氨基酸的共价配对。全基因组测序的广泛应用揭示了与疾病相关的mtARS编码基因的多种变异，这些变异主要在需要高能量的器官中观察到。尽管酶具有共同的生化作用，但mtARS变异患者的广泛临床表现涉及不同的生理系统然而，mtARS编码基因的变异在很大程度上与中枢神经系统有关。只有一些变异，包括AARS2、VARS2、PARS2和YARS2，被确定为人类心肌病的病因，但病理机制尚不清楚。所有已知的FARS2变异仅与中枢神经系统相关疾病有关，如遗传性痉挛性截瘫FARS2变异与其他全身性疾病的相关性尚未报道。FARS2缺乏通过破坏线粒体稳态和线粒体质量控制系统引起心肌病（Credit: Circulation）线粒体功能、形态和质量的维持，也称为线粒体稳态，对心脏功能和衰老至关重要线粒体质量控制(MQC)系统是一个强大的协调器，在基础条件和各种应激条件下(如心脏重构)维持线粒体稳态。复杂的信号通路构成了MQC系统，包括线粒体裂变、融合和线粒体相关的自噬。已有研究揭示了MQC系统的关键功能分子在心脏功能和应激诱导重构中的作用。然而，mtARS相关HCM的分子机制尚不清楚，线粒体稳态变化和MQC系统的作用也不清楚。该研究发现FARS2是遗传性心肌病的潜在致病基因。FARS2缺乏通过损害线粒体稳态和破坏MQC系统导致心脏肥厚。该研究不仅强化了FARS2在心脏病中的生物学功能，而且为线粒体翻译缺陷相关HCM的潜在预防和FARS2相关心肌病的治疗靶点提供了新的见解。原文链接https://www-ahajournals-org.libproxy1.nus.edu.sg/doi/10.1161/CIRCULATIONAHA.123.064489责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

Company will perform plasmid DNA production in support of early phase trials for SPG56 Hereditary Spastic Paraplegia WILMINGTON, Mass.--(BUSINESS WIRE)-- Charles River Laboratories International, Inc. (NYSE: CRL) and Genetic Cures for Kids Inc (GC4K), an Australian non-profit foundation focused on research programs and clinical trials to find cures for rare diseases, today announced a plasmid DNA contract development and manufacturing organization (CDMO) collaboration. Founded in 2021 by Golden and Chris Whitrod, parents of now 4 year old Tallulah Moon, GC4K’s first mission, known as Our Moon’s Mission, is to develop a gene therapy for the treatment of Hereditary Spastic Paraplegia Type 56 (SPG56). SPG56 is a debilitating neurodegenerative disease that robs children of the ability to walk, talk, and move independently. What is SPG56? SPG56 manifests as a progressive neurological disease characterised by varying degrees of spasticity and muscle weakness. This degenerative disease typically begins with motor and cognitive regression in childhood and continuously worsens through life. Additional clinical manifestations include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, seizures, and visual impairment. Tragically, there is currently no treatment for this ultra-rare genetic disease. In addition, limited access to genetic testing means diagnoses are hard to achieve and as such, fewer than one in 1 million people have ever been diagnosed with SPG56 globally. GC4K is leading a gene therapy program that aim not to only cure SPG56, but to create a replicable framework that paves the way to develop treatments for some of the 7,000 other genetic diseases in the world. Plasmid DNA Manufacturing Services GC4K will leverage Charles River’s established plasmid platform, eXpDNA™, and premier expertise in plasmid DNA production, including High Quality (HQ) plasmid which combines key features of good manufacturing practice (GMP) manufacture with a rapid turnaround to accelerate time to clinic. As a critical starting material in the development of cell and gene therapies, in 2022 Charles River opened a state-of-the-art HQ Plasmid Manufacturing Center of Excellence dedicated to addressing global supply shortages and support the growing needs of customers. In recent years, Charles River has significantly broadened its cell and gene therapy portfolio to simplify complex supply chains and meet growing demand for plasmid DNA, viral vector, and cell therapy services. Combined with the Company’s legacy testing capabilities, Charles River offers a comprehensive “concept-to-cure” advanced therapies solution. To learn more about plasmid DNA production, watch Advancements in Manufacturing for Rapid Delivery of pDNA Starting Materials, presented by Andrew Frazer, PhD, Associate Director, Scientific Solutions, Gene Therapy CDMO Services, on-demand: Approved Quotes “The opportunity to work with GC4K is exactly why we do what we do, playing a role in delivering potentially curative treatments to patients suffering with an ultra-rare disease. We are excited to support the team as they work through the next stage of their program development.” - Kerstin Dolph, Corporate Senior Vice President, Biologics Solutions, Charles River “What was once a tragic diagnosis, has the potential to become a triumph, as we draw nearer to finding a cure for SPG56. With the advancement of this groundbreaking treatment, our partnership with Charles River is bringing us closer to aiding children like Tallulah, who, until now, have faced the daily hardships of SPG56 without any glimmer of hope. We're truly excited to have the backing of this skilled team as we gear up to produce this historic treatment. By making this announcement on Giving Tuesday, we are giving thanks to Charles River. This symbolic occasion not only commends the generosity of CRL in supporting GC4K’s quest to cure SPG56, but also to recognizes the broader goal that our partnership is striving for - a brighter future for all children living with rare genetic diseases." - Golden Whitrod, Tallulah Moon’s mother and Co-Founder and President, Genetic Cures for Kids, Inc. About Charles River Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit . Genetic Cures for Kids, Inc., and Our Moon’s Mission GC4K is a family-driven research foundation at the forefront of genetic research, with a primary objective to not only develop a cure for SPG56 but also to establish a reproducible framework that can catalyze the development of treatments for some of the 7,000 known genetic diseases worldwide. The foundation's campaign to cure SPG56 is "Our Moon's Mission", named in honor of the founders’ daughter Tallulah Moon, who lives with SPG56. By leveraging crowdfunding to assemble an expert international research team, which has since gained recognition and funding from the Australian Government and is guided by an Independent Scientific Advisory Board, GC4K aims to expedite the development of effective SPG56 therapies for clinical use. Additionally, the foundation is dedicated to advocating for 'rare families' and increasing awareness of rare diseases. To learn more about GC4K's commitment to advancing genetic research and to support the foundation's mission to cure SPG56, please visit

THURSDAY, July 27, 2023 -- Many parents in the United States aren't installing child car seats correctly, a new study finds. Errors in car seat installation are common, even for seats that have a 5-star rating for features like ease of use, researchers found. The study found that fewer errors were detected when parents installed seats that had higher ratings, but researchers recommend that parents seek out safety technicians to learn the proper techniques for seat installation. Child restraint systems cut the risk of crash injuries by 50% to 85%, but only if properly used, the researchers noted. "New parents often receive training on car seat installation before the baby is born," said researcher Dr. Michelle Macy , an emergency medicine physician at Ann & Robert H. Lurie Children’s Hospital of Chicago. "However, it would be beneficial for them to take advantage of the available resources after the child’s birth as well, especially during the transition from infant carrier to a rear-facing car seat, and then again when switching the seat to face forward," she said in a hospital news release. For the study, Macy and her colleagues analyzed data from Safe Kids Illinois seat check records from 2015 through 2019. The most common errors were for seats installed with seat belts (70%) and the least common for recline angle (37%). One of the more common errors that were found around 50% of the time, even with 5-star rated car seats, involved the top tether on forward-facing car seats. The top tether is the strap on top of the seat that needs to be hooked to an anchor point on the vehicle. Often parents do not attach the strap or hook it in the wrong location. "Overall, our study results show that parents can rely on the car seat rating system when choosing an appropriate car seat for their child," Macy said. "They just need to be aware that installation and use errors can still occur even with the top-rated car seats. We encourage parents to get help from a certified technician to ensure their child’s safety on the road." The report was published July 21 in the journal Traffic Injury Prevention . The National Highway Traffic Safety Administration website provides a resource directory by zip code to help parents connect with a nearby certified child passenger safety technician. Sources Ann and Robert H. Lurie Children's Hospital of Chicago, news release, July 21, 2023 Posted July 2023