Pathogenesis Informs Therapy for Glycosphingolipid and Glycoprotein Disorders

发病机制为糖鞘脂和糖蛋白疾病的治疗提供依据

• 批准号: 10911738
• 负责人: Cynthia Tifft
• 金额: $ 115.52万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/10911738
• 关键词: Adult; Age; Agreement; Alzheimer' s Disease; Biogenesis; Blood; Brain; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Cell model; Cells; Cerebrospinal Fluid; Cerebrum; Child; Childhood; Clinic; Clinical; Clinical Management; Collaborations; Coupled; Data; Development; Diagnosis; Disease; Disease Progression; Enrollment; Family; Fetus; Fibroblasts; Functional Magnetic Resonance Imaging; Functional disorder; GLB1 gene; Galactosialidosis; Gangliosides; Gangliosidoses GM2; Gangliosidosis GM1; Gene Expression; Gene Transfer; Gene therapy trial; Generations; Genes; Glycoprotein Degradation Pathway; Glycoproteins; Glycosphingolipids; Human; Infant; Intervention; Intervention Trial; Intravenous; Laboratories; Lead; Lipomucopolysaccharidoses; Longevity; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Massachusetts; Mission; Molecular; Multicenter Trials; Mus; NIH Mouse; Natural History; Neurodegenerative Disorders; Neurologist; Neuronal Differentiation; Neurons; Nursing Research; Organoids; Outcome Measure; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Postdoctoral Fellow; Pregnancy; Publishing; Rare Diseases; Research; Sandhoff Disease; Site; Symptoms; Tay-Sachs Disease; Testing; Tissues; Transcript; United States National Institutes of Health; Universities; Urine; Work; autosome; biobank; blood-brain barrier crossing; candidate validation; cohort; data sharing; design; enzyme deficiency; first-in-human; gene therapy; genome wide screen; imaging facilities; induced pluripotent stem cell; infancy; inhibitor; loss of function; medical schools; mouse model; novel therapeutics; pharmacologic; programs; small molecule; synaptogenesis; transcription factor; transcriptome; trial design; vector

The mission of the Glycosphingolipid and Glycoprotein Disorders Unit is to understand the disease progression and molecular pathogenesis of rare disorders in glycosphingolipid and glycoprotein degradation. Understanding these ultra-rare, autosomal recessive, uniformly fatal disorders we believe will provide a window to understanding more common neurodegenerative disorders. The laboratory and clinical programs of the unit are tightly coupled and allow for the generation and testing of new hypotheses and treatments. Postdoctoral fellow Dr. Ted Han has conducted a genome-wide screen for consequences in gain and loss-of-function of transcription factor EB (TFEB) a master regulator of lysosomal biogenesis and function. Pathways which modulate TFEB activity may represent sites for pharmacologic intervention in multiple lysosomal disorders. By using CRISPR/Cas9 technologies, research fellow Dr. Raluca Nicolai has created a mouse model of GM1 gangliosidosis and with extensive phenotyping has demonstrated that it most closely resembles our Type II GM1 patients. With collaborators from the NIH Mouse Imaging Facility (MIF), she has performed magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and functional MRI on live mice at key timepoints in disease progression; a first for the NIH MIF. Our overarching natural history study has enrolled over 100 patients with GM1 and GM2 gangliosidosis (Tay-Sachs (TSD) and Sandhoff diseases (SD)), sialidosis, and galactosialidosis. We maintain and make available to collaborators a large biorepository of blood, urine, cerebrospinal fluid, and primary fibroblasts and, when possible, tissues on deceased patients. In a collaborative project, Drs. Han and Nicoli have performed transcriptome analysis on 4 brain regions from two 17-week gestation fetuses with TSD and age-matched control tissues and found that TSD brains are deficient in many transcripts notably neuronal synapse formation. This aligns with our previous work showing lack of neuronal differentiation in human cerebral organoids derived from iPS cells from a patient with infantile Sandhoff disease. Significant differences in early brain development of GM2 infants will have obvious implications for type and timing of therapy for these patients and may extend to other lysosomal storage disorders involving the brain. Data collected from the natural history study has provided new understanding of disease progression in GM1 and GM2 disease and we have published reviews on both disorders. The natural history study has also elucidated robust outcome measures for two interventional trials currently in progress. NCT03952637 is a first-in-human intravenous AAV9-GLB1 gene therapy for children with Type I and II GM1 gangliosidosis. The study was the culmination of a 10-year collaboration with colleagues Dr. Miguel Sena-Esteves and Dr. Heather Gray-Edwards at U. Massachusetts Medical School, Dr. Doug Martin at Auburn University. Under the guidance of primary clinician Dr. Precilla DSouza and research nurse Jean Johnston, twelve patients have safely received the gene transfer. Outcome measures now extend to three years post gene therapy. Additional vector is being prepared and a phase 2/3 pivotal trial is in the planning stages. NCT04221451, the AMETHIST Study, sponsored by Sanofi Genzyme utilizes a proprietary substrate reduction molecule that crosses the blood brain barrier and blocks the first committed step in ganglioside synthesis. Our Unit is the lead site for the trial and furnished the patient data for trial design and outcome measures under cooperative research and data sharing agreements. Research nurse Andrea Ashton, primary clinician Catherine Groden, and neurologist Dr. Camilo Toro oversee the largest cohort of GM2 patients in this multi-national study.

神经鞘糖脂和糖蛋白紊乱组的任务是了解神经鞘糖脂和糖蛋白降解的罕见疾病的疾病进展和分子发病机制。了解这些超罕见、常染色体隐性、一致致命的疾病，我们相信将为了解更常见的神经退行性疾病提供一个窗口。该单位的实验室和临床项目紧密结合，允许产生和测试新的假设和治疗方法。 博士后研究员Ted han博士对转录因子EB(TFEB)的获得和功能丧失的后果进行了全基因组筛查，TFEB是溶酶体生物发生和功能的主要调节因子。调节TFEB活性的途径可能代表了药物干预多发性溶酶体疾病的部位。通过使用CRISPR/Cas9技术，研究员Raluca Nicolai博士创建了GM1神经节苷脂沉积症的小鼠模型，并通过广泛的表型鉴定表明，它与我们的II型GM1患者最相似。她与NIH老鼠成像设备(MIF)的合作者一起，在疾病进展的关键时间点对活体小鼠进行了磁共振成像(MRI)、磁共振波谱(MRS)和功能磁共振成像；这是NIH MIF的第一次。 我们的主要自然病史研究招募了100多名GM1和GM2神经节苷脂沉积症(Tay-Sachs(TSD)和Sandhoff病(SD))、唾液酸沉着症和半唾液酸沉着症的患者。我们维护并向合作者提供血液、尿液、脑脊液和原代成纤维细胞的大型生物库，如果可能的话，还包括已故患者的组织。在一个合作项目中，韩博士和尼科利博士对两个患有TSD和年龄匹配的对照组织的17周妊娠胎儿的4个大脑区域进行了转录组分析，发现TSD大脑缺乏许多转录本，尤其是神经元突触形成。这与我们之前的工作一致，显示从一名婴儿桑德霍夫病患者的iPS细胞中提取的人脑器官缺乏神经元分化。GM2婴儿早期大脑发育的显著差异将对这些患者的治疗类型和治疗时机产生明显影响，并可能延伸到其他涉及大脑的溶酶体储存障碍。 从自然历史研究中收集的数据为GM1和GM2疾病的疾病进展提供了新的理解，我们发表了对这两种疾病的综述。这项自然历史研究还阐明了目前正在进行的两项干预试验的稳健结果衡量标准。NCT03952637是首个人类静脉注射AAV9-GLB1基因疗法，用于治疗I型和II型GM1神经节苷脂沉积症。这项研究是与美国马萨诸塞州医学院的米格尔·塞纳-埃斯特维斯博士和希瑟·格雷-爱德华兹博士以及奥本大学的道格·马丁博士长达10年的合作的结果。在首席临床医生Precilla DSouza博士和研究护士Jean Johnston的指导下，12名患者已经安全地接受了基因转移。结果衡量标准现在延伸到基因治疗后三年。正在准备更多的载体，2/3阶段的关键试验正在规划阶段。由赛诺菲Genzyme赞助的AMETHIST研究NCT04221451利用一种专利底物还原分子跨越血脑屏障，阻止神经节苷脂合成的第一步。我们的单位是试验的牵头站点，并根据合作研究和数据共享协议为试验设计和结果测量提供患者数据。研究护士安德里亚·阿什顿、首席临床医生凯瑟琳·格罗登和神经学家卡米洛·托罗博士负责监督这项跨国研究中最大的GM2患者队列。

项目成果

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment.

• DOI: 10.1016/j.neulet.2021.136195
• 发表时间: 2021-11-01
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Toro C;Zainab M;Tifft CJ
• 通讯作者: Tifft CJ

Myoclonus generators in sialidosis.

• DOI: 10.1016/j.cnp.2022.05.004
• 发表时间: 2022
• 期刊: Clinical neurophysiology practice
• 影响因子: 1.7

GM1 Gangliosidosis-A Mini-Review.

• DOI: 10.3389/fgene.2021.734878
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Nicoli ER;Annunziata I;d'Azzo A;Platt FM;Tifft CJ;Stepien KM
• 通讯作者: Stepien KM

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

• DOI: 10.1126/sciadv.ade1463
• 发表时间: 2023-03-10
• 期刊: Science advances
• 影响因子: 13.6

The Complement Regulator Susd4 Influences Nervous-System Function and Neuronal Morphology in Mice.

补体调节剂 Susd4 影响小鼠的神经系统功能和神经元形态。

• DOI: 10.1016/j.isci.2020.100957
• 发表时间: 2020
• 期刊: iScience
• 影响因子: 5.8
• 作者: Zhu,Hongling;Meissner,LauraE;Byrnes,Colleen;Tuymetova,Galina;Tifft,CynthiaJ;Proia,RichardL
• 通讯作者: Proia,RichardL