Clinical Pursuits by the NHGRI Office of the Clinical Director

NHGRI 临床主任办公室的临床追求

基本信息

批准号：
10022466
负责人：
William Gahl
金额：
$ 12.25万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10022466
关键词：
Acidity Adolescent Albinism Animal Model Annual Reports Apoenzymes Ataxia Biochemical Biochemical Genetics Brain CRISPR screen Case Study Cells Cerebrum Child Chlorides Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Coloboma Congenital Heart Defects Congenital cerebellar hypoplasia Congenital disorders of glycosylation Cornea Cysteine-tRNA ligase Defect Development Developmental Delay Disorders Diagnosis Disease Disease Progression Doctor of Philosophy Dysarthria Enrollment Epilepsy Evaluation Face Family Functional disorder Gangliosidoses GM2 Gangliosidosis GM1 Genes Genetic Genetic Diseases Genetic Transcription Glycosphingolipids Golgi Apparatus Grant Hair Head Human Individual Intravenous Iron Knockout Mice Knowledge Lamin B1 Liver Lung diseases Lysosomal Storage Diseases Lysosomes Massachusetts Mediating Medical Medical Genetics Medical Records Menkes Kinky Hair Syndrome Metabolism Metals Microcephaly Modeling Molecular Motor Multiprotein Complexes Mutate Mutation Nail plate National Human Genome Research Institute Natural History Neurodevelopmental Disorder Neuronal Ceroid-Lipofuscinosis Normal tissue morphology Organ Organelles Organoids Patient Recruitments Patients Phenotype Pilot Projects Program Reviews Proteins Protons Rare Diseases Recruitment Activity Regulation Reporting Research Personnel Sandhoff Disease Schedule Signal Transduction Syndrome Tay-Sachs Disease Testing Tissue-Specific Gene Expression Uniparental Disomy United States National Institutes of Health Universities Variant Vesicle WD Repeat base biobank boys brain tissue clinical research site cohort developmental disease epileptic encephalopathies exome first-in-human gain of function mutation gene therapy girls hypocupremia induced pluripotent stem cell infancy leukodystrophy member metabolomics novel oxidation pre-clinical precision medicine programs sensory neuropathy small molecule therapeutic target trafficking transcription factor transcriptome sequencing translational study

项目摘要

In the NHGRI Office of the Clinical Director, Cynthia Tifft, MD, PhD, heads the Unit on Glycosphingolipid Storage Disorders, which performs translational studies on Tay-Sachs and Sandhoff diseases and GM1 gangliosidosis. Since its inception in 2009, the Unit has been actively recruiting patient with GM1 and GM2 gangliosidosis as part of a natural history study. Information gained from this study along with pre-clinical data from collaborators at the University of Massachusetts and Auburn University was used to file an IND in February, 2019 for intravenous AAV9-mediated gene therapy for patients with type II GM1 gangliosidosis. The first patient under this IND received first-in-human gene therapy in May, 2019 and an additional 5 individuals are scheduled to be enrolled by the end of the year. In basic studies, the Unit used cerebral organoids from patient-derived induced pluripotent stem cells (iPSC) to test gene therapy and small molecules to treat the fatal lysosomal storage diseases, GM1 and GM2 gangliosidoses. Specifically, the Unit is using RNA expression analysis in the cerebral organoids and brain tissue to explore the earliest perturbations in brain development resulting from mutations in HEXA and HEXB. The Unit is a recipient of two NISC pilot project grants. The first is analyzing exome sequences from a cohort of Type II GM1 gangliosidosis patients to identify variants in 1300 lysosomal-related genes as potential modifiers of disease presentation. The second project involves performing RNAseq on developing brain tissues from two patients with Tay-Sachs disease to analyze differential gene expression, and comparing it to that of normal tissues. The Unit is also phenotyping a CRISPR-generated GM1 knock out mouse that mirrors the manifestations and disease progression in patients with Type II (juvenile) GM1; this will greatly aid the lab and the field in identifying therapeutic targets for GM1 disease. Lastly, the unit is using a CRISPR-based screen for transcription factor EB (TFEB) signaling to identify genes involved in lysosome-related cell regulation. A second clinical initiative within the Office of the Clinical Director involves the NIH Undiagnosed Diseases Program (UDP), a model for Precision Medicine that provides answers to patients with mysterious conditions that have eluded diagnosis and advances medical knowledge. The UDP is part of the Undiagnosed Diseases Network (UDN), a national consortium of 12 clinical sites, a coordinating center, sequencing center, biorepository, two model organism cores, and a metabolomics core. Each year the NIH UDP reviews approximately 350 medical records and accepts 100-125 patients for thorough medical and genetic evaluations at the NIH Clinical Center. Rare disorders are diagnosed and new diseases are discovered. In 2019, UDP projects revealed the genetic bases of 7 diseases. Specifically, Saul-Wilson Syndrome was shown to be caused by a monoallelic mutation in COG4, which encodes a protein in the Conserved Oligomeric Golgi complex responsible for retrograde vesicle trafficking within the Golgi. Another study described a new disorder of developmental delay, liver abnormalities, dysmorphic features, and woolly hair associated with biallelic variants in CCDC47. A third new disease, characterized by facial dysmorphisms, congenital heart defects, and neurodevelopmental abnormalities, was associated with biallelic mutations in TMEM94. A fourth disorder described by the UDP was a combination of albinism, developmental delay, and organ storage caused by dysfunction of lysosomes and lysosome-related organelles. This occurred because of increased lysosomal acidity created by a gain-of-function mutation in CLCN7, encoding a chloride transporter that determines the influx of protons into lysosomes. Another case involved a boy with kinky hair reminiscent of Menkes disease, a copper deficiency disorder. The child had biallelic mutations in HEPHL1, whose function was determined to include oxidation of ferrous to ferric iron, allowing this metal to be incorporated into its apoenzymes. A sixth new disease involved multisystem dysfunction in a girl with a mutated SLC12A2 gene. Finally, members of the UDP described a new disorder of epilepsy, colobomas, dysmorphisms, developmental delay, and cerebellar hypoplasia due to monoallelic mutations in WDR37, which encodes a protein whose WD repeats facilitate the formation of multiprotein complexes. UDP members also assisted in the description of a new disease of developmental delay, microcephaly, and brittle nails and hair due to biallelic mutations in cysteinyl tRNA synthetase. They revealed the molecular, clinical, and biochemical bases of SLC25A2 Congenital Disorder of Glycosylation, characterizing 30 previously unreported cases of this disease, and expanded the known phenotypes of COPA syndrome, a pulmonary disorder, and late infantile ceroid lipofuscinosis, a neurodevelopmental disorder due to CLN6 mutations. UDP members reported a case of Early Infantile-onset Epileptic Encephalopathy 28 due to deletion of the WWOX gene related to uniparental disomy. One family had motor delays, coloboma and corneal defects associated with a novel TENM3 mutation, and another had dysarthria, ataxia, and sensory neuropathy related to COX20 variants. The UDP collaborated with world experts in describing atypical autosomal dominant leukodystrophy due to an upstream deletion of lamin B1; previously reported cases were due to lamin B1 duplications. These projects were pursued in collaboration with the Section on Human Biochemical Genetics in the Medical Genetics Branch of NHGRI, and are discussed in the Sections annual report as well.

在 NHGRI 临床主任办公室，辛西娅·蒂夫特 (Cynthia Tifft) 医学博士、哲学博士领导着鞘糖脂储存障碍部门，该部门对泰萨克斯病、桑德霍夫病和 GM1 神经节苷脂贮积症进行转化研究。自 2009 年成立以来，该科室一直在积极招募 GM1 和 GM2 神经节苷脂沉积症患者，作为自然史研究的一部分。从这项研究中获得的信息以及来自马萨诸塞大学和奥本大学合作者的临床前数据被用来于 2019 年 2 月提交 IND，用于针对 II 型 GM1 神经节苷脂沉积症患者进行静脉 AAV9 介导的基因治疗。该 IND 下的第一位患者于 2019 年 5 月接受了首次人体基因治疗，另外 5 名患者计划在今年年底前入组。在基础研究中，该部门使用来自患者的诱导多能干细胞 (iPSC) 的脑类器官来测试基因疗法和小分子来治疗致命的溶酶体贮积病、GM1 和 GM2 神经节苷脂沉积症。具体来说，该部门正在利用大脑类器官和脑组织中的 RNA 表达分析来探索 HEXA 和 HEXB 突变引起的大脑发育的最早扰动。该单位获得了两项 NISC 试点项目赠款。第一个是分析 II 型 GM1 神经节苷脂沉积症患者队列的外显子组序列，以确定 1300 个溶酶体相关基因的变异作为疾病表现的潜在修饰因子。第二个项目涉及对两名泰萨斯病患者的发育中的脑组织进行 RNAseq，以分析差异基因表达，并将其与正常组织进行比较。该部门还在对 CRISPR 生成的 GM1 敲除小鼠进行表型分析，该小鼠反映了 II 型（幼年）GM1 患者的表现和疾病进展；这将极大地帮助实验室和领域确定 GM1 疾病的治疗靶点。最后，该单位正在使用基于 CRISPR 的转录因子 EB (TFEB) 信号筛选来识别参与溶酶体相关细胞调节的基因。临床主任办公室的第二项临床举措涉及 NIH 未诊断疾病计划 (UDP)，这是一种精准医学模型，可为患有无法诊断的神秘疾病的患者提供答案，并提高医学知识。 UDP 是未确诊疾病网络 (UDN) 的一部分，该网络是一个由 12 个临床中心、一个协调中心、测序中心、生物样本库、两个模式生物核心和一个代谢组学核心组成的国家联盟。 NIH UDP 每年都会审查大约 350 份医疗记录，并接受 100-125 名患者在 NIH 临床中心进行彻底的医学和遗传评估。诊断出罕见疾病并发现新疾病。 2019年，UDP项目揭示了7种疾病的遗传基础。具体来说，Saul-Wilson 综合征是由 COG4 中的单等位基因突变引起的，COG4 编码保守寡聚高尔基复合体中的一种蛋白质，负责高尔基体内逆行囊泡运输。另一项研究描述了与 CCDC47 中双等位基因变异相关的一种新的发育迟缓、肝脏异常、畸形特征和羊毛状毛发疾病。第三种新疾病以面部畸形、先天性心脏病和神经发育异常为特征，与 TMEM94 的双等位基因突变有关。 UDP 描述的第四种疾病是由溶酶体和溶酶体相关细胞器功能障碍引起的白化病、发育迟缓和器官储存的组合。发生这种情况的原因是 CLCN7 的功能获得性突变导致溶酶体酸度增加，CLCN7 编码一种氯离子转运蛋白，决定质子流入溶酶体。另一个病例涉及一个头发卷曲的男孩，让人想起门克斯病，一种铜缺乏症。该孩子的 HEPHL1 存在双等位基因突变，其功能被确定为包括将亚铁氧化为三价铁，从而使这种金属能够掺入其脱辅基酶中。第六种新疾病涉及 SLC12A2 基因突变女孩的多系统功能障碍。最后，UDP 成员描述了一种新的疾病，包括癫痫、缺损、畸形、发育迟缓和小脑发育不全，这是由于 WDR37 的单等位基因突变所致，WDR37 编码一种蛋白质，其 WD 重复序列促进多蛋白复合物的形成。 UDP 成员还协助描述了一种新疾病，即由于半胱氨酰 tRNA 合成酶的双等位基因突变而导致的发育迟缓、小头畸形以及指甲和头发脆弱。他们揭示了 SLC25A2 先天性糖基化障碍的分子、临床和生化基础，描述了 30 例以前未报告的这种疾病的病例，并扩展了 COPA 综合征（一种肺部疾病）和晚期婴儿蜡质脂褐质沉着症（一种由CLN6 突变。 UDP成员报告了一例婴儿早期发病的癫痫性脑病28，其原因是与单亲二体性相关的WWOX基因缺失。其中一个家庭患有与新型 TENM3 突变相关的运动迟缓、缺损和角膜缺陷，另一个家庭则患有与 COX20 变异相关的构音障碍、共济失调和感觉神经病。 UDP 与世界专家合作，描述了由于核纤层蛋白 B1 上游缺失所致的非典型常染色体显性脑白质营养不良；先前报道的病例是由于核纤层蛋白 B1 重复所致。这些项目是与 NHGRI 医学遗传学分部人类生化遗传学科合作开展的，并在该科的年度报告中进行了讨论。