Lubs X-Linked Mental Retardation Syndrome

NEWS 近日，一项 “评价LY-M001注射液单次静脉输注I型戈谢病青少年患儿中的安全性和有效性的前瞻性、单中心、开放、单臂临床研究”在国家儿童医学中心、上海交通大学医学院附属上海儿童医学中心顺利开展并取得疗效。 本项目由内分泌遗传代谢科、临床研究病区王秀敏教授作为主要研究者发起，由内分泌遗传代谢科、临床研究病区、血液肿瘤科、放射科等多学科团队共同参与。今年8月，医学团队成功为一名15岁I型戈谢病青少年患者完成了给药治疗。这也是全球首例接受基因治疗的I型戈谢病青少年患者。 戈谢病（Gaucher disease，GD）是一种由葡萄糖脑苷脂酶（GBA）基因变异引起的常染色体隐性遗传性溶酶体贮积病,表现为多系统的脂质沉积，受累的血液、肝脾、骨骼及神经系统功能受损而出现相应的临床表现，导致肝脾肿大、贫血、血小板减少、骨痛以及骨骼病变，发育迟缓而可能终身残疾甚至死亡。戈谢病目前主要的治疗方法有酶替代治疗、造血干细胞移植、底物抑制疗法以及基因治疗。基因治疗是输注以病毒为载体的基因治疗产品，给药后可特异性转导靶器官，并在靶器官中长期表达GCase蛋白，戈谢病患者体内各脏器蓄积的有害糖脂代谢物会被GCase蛋白降解，从而有效治疗戈谢病。 目前，该受试者已完成治疗后八周的密切随访。孩子状态良好，未见明显不良反应发生，已停止昂贵的酶替代治疗，酶活性恢复正常，生活质量较前明显提高。 2022年2月，上海儿童医学中心临床研究病区正式启用，以患者为中心，围绕儿童罕见病开展前沿性临床应用探索，打破罕见病治疗瓶颈，破解我国儿童用药短缺“卡脖子”问题。作为国家儿童医学中心和上海市基因治疗临床医学研究中心，医院积极致力于国产创新药械的开发与应用，特别是罕见病基因治疗的相关临床研究。已开展的世界首次用于人体的治疗芳香族 L-氨基酸脱羧酶缺乏症基因治疗项目已完成前期IIT研究并进入注册临床阶段。目前，包括针对I型戈谢、杜氏肌营养不良、MECP2重复综合征和急性髓系白血病等疾病的多个基因治疗项目均已顺利开展。 上海儿童医学中心完成全球首例I型戈谢病青少年患者基因治疗，不仅标志着基因治疗技术的重大突破，也为罕见病治疗带来了新的希望和曙光，同时展示了我国在医疗创新和跨学科合作方面的实力和潜力。LY-M001注射液是由凌意（杭州）生物科技有限公司研发的创新型基因治疗药物；派真生物很荣幸能够助推凌意生物的AAV基因治疗药物进展，为项目提供了高质量的CMC服务！未来，派真生物也将在基因治疗领域继续深耕，为药物创新提供一站式CMC解决方案，助力更多优质项目推进。 关于LY-M001注射液 LY-M001注射液是中国首个自主研发，针对I型和III型戈谢病的AAV基因治疗药物，属于治疗用生物制品1类创新型生物制品。该产品以重组腺相关病毒rAAV为载体，通过单次静脉输注给药后即可表达患者所需的葡萄糖脑苷脂酶。凌意生物开发了拥有完全自主知识产权的改良型葡萄糖脑苷脂酶基因治疗载体，可在体内长期稳定表达并降解有害糖脂代谢物，从而达到长期治疗戈谢病的目标。 关于凌意生物 凌意生物成立于2021年2月，是全球领先的单基因遗传病创新药物开发公司。公司拥有国际一流的基因疗法发现、研究开发及产业化团队，致力于First-In-Class基因治疗管线的研发和产业化。公司立足源头创新，聚焦代谢、中枢神经系统、眼科等临床急需的疾病领域，从遗传病动物模型等关键技术入手，以最高的质量标准为患者提供一次性解决方案。 凌意生物在研戈谢病AAV基因治疗药物LY-M001注射液于2024年1月获得NMPA和FDA的IND新药临床试验批件并已正式开展注册临床I/II 期试验，同时也已获FDA的孤儿药ODD资格认定。目前LY-M001注射液已完成数例戈谢病成人和儿童患者给药，初步数据显示LY-M001注射液在安全性和有效性方面均有良好表现。 转自：凌意生物 关于派真生物

PNRI's Landmark Study Reveals DNA Rearrangement's Role in Genetic Disorders, Paving Way for New Treatments SEATTLE, June 21, 2024 /PRNewswire/ -- Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health1 and published in Cell Genomics, reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. Understanding the Study Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study examines how these complex rearrangements form and their impact on human health. Key Findings The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications. They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome. These switches occur within pairs of inverted repeats—mirror-image DNA sections that confuse the repair machinery. This can lead to using the wrong template, disrupting gene function and contributing to genetic disorders. Structural Diversity: The study found that inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes. Gene Dosage Impact: These rearrangements can alter the number of copies of certain genes, known as gene dosage. The correct number of gene copies is crucial for normal human development and function. Changes in gene dosage can cause diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder. Mapping Breakpoints: By using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates leading to an altered number of genes including MECP2. Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2 duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome. Implications for Medical Research and Treatment "This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Cláudia Carvalho, PNRI's lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes." About PNRI: Pacific Northwest Research Institute (PNRI) is a nonprofit biomedical research institute, where scientists are using innovative approaches in genetics and genomics to tackle some of the most difficult problems in science and medicine. The institute was founded 67 years ago in Seattle, Washington, as a place where scientists were free to pursue discoveries that promised the highest chance of improving human health. The goal was at the beginning, and remains today, to conduct foundational science leading to impactful medical innovations. To learn more, visit pnri.org. 1 Research reported in this press release was supported in part by National Institute of General Medical Sciences of the National Institutes of Health under award number R01132589.

Researchers have uncovered how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. The study reveals that during DNA repair, segments may switch templates within inverted repeats, leading to structural variations and gene dosage alterations, impacting conditions like MECP2 duplication syndrome. This discovery opens new avenues for understanding and treating rare genetic disorders. Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health and published in the journal Cell Genomics, reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. Understanding the Study Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health. Key Findings The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications. They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome. These switches occur within pairs of inverted repeats -- sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders. Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome. Implications for Rare Disease Research and Treatment "This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Cláudia Carvalho, PNRI's lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes." These findings are being applied in a follow-up study led by Baylor's Davut Pehlivan, M.D., investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.