Clinical Investigations of Inborn Errors of Metabolism

先天性代谢缺陷的临床研究

• 批准号: 10691799
• 负责人: Forbes Porter
• 金额: $ 92.23万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 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/10691799
• 关键词: 7-dehydrocholesterol; Adolescent; Adult; Affect; Age; Basic Science; Behavioral; Belief; Biochemical Process; Biocompatible Materials; Biological; Biological Markers; Blindness; Brain; CLN3 gene; Cell physiology; Cerebellar Diseases; Child; Childhood; Cholesterol; Clinical Data; Clinical Protocols; Clinical Research; Clinical Sciences; Collaborations; Collection; Complement; Country; Creatine; Cyclodextrins; Cysteine; Dementia; Developmental Process; Dietary Cholesterol; Disease; Dysmorphology; Enrollment; Enzymes; Face; Fireflies; Foundations; Functional disorder; Funding; Future; Gastrointestinal tract structure; Genes; Genetic Diseases; Genital; Genitalia; Goals; Growth; Heart; Hereditary Disease; Impaired cognition; Impairment; Inborn Errors of Metabolism; Incidence; Individual; Infant; Intravenous; Kidney; Laboratories; Learning; Limb structure; Link; Lung; Lysosomal Storage Diseases; Medical Research; Molecular; Morbidity - disease rate; Mutation; NPC1 gene; National Center for Advancing Translational Sciences; Natural History; Neonatal Screening; Neurodegenerative Disorders; Niemann-Pick Diseases; Observational Study; Obsessive compulsive behavior; Participant; Pathologic; Patient Care; Patients; Phenotype; Problem behavior; Process; Proteins; Psyche structure; Research; Safety; Seizures; Simvastatin; Smith-Lemli-Opitz Syndrome; Spielmeyer-Vogt Disease; Structural defect; Supplementation; Supraoptic Vertical Ophthalmoplegia; Syndrome; Therapeutic; Therapeutic Intervention; Therapeutic Trials; Translational Research; Vorinostat; Work; autistic; behavioral phenotyping; biomarker identification; boys; clinical care; clinical investigation; clinical outcome measures; cohort; congenital anomaly; creatine transporter; efficacy evaluation; improved; insight; malformation; mortality; pediatric patients; progressive neurodegeneration; rare genetic disorder

This project supports the clinical science research conducted by the Section on Molecular Dysmorphology. It complements and synergizes with the basic/translational science conducted under project HD008988. It consolidates and extends HD008824 and HD008825. This project includes both natural history/observational and therapeutic trials genetic disorders cause by inborn errors of metabolism. The natural history/observational studies include deep phenotyping and collection of biomaterials for biomarker identification and characterization. The disorders currently being studied include Smith-Lemli-Opitz syndrome, Niemann-Pick disease, type C, CLN3 disease (Batten Disease) and Creatine Transporter Deficiency. Our goals include improving clinical care, identifying developing therapeutic interventions. Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis with an incidence on the order of 1/50,000. SLOS is an autosomal recessive multiple congenital anomaly/cognitive impairment syndrome characterized by facial dysmorphology, growth retardation and variable structural anomalies of the heart, lungs, brain gastrointestinal tract, genitalia, kidneys, and limbs. Mutations of DHCR7, the gene that encodes an enzyme that converts 7-dehydrocholesterol to cholesterol underly SLOS. Individual with SLOS manifest variable cognitive impairment ranging from mild learning difficulties to profound mental dysfunction. SLOS has a distinct behavior phenotype which includes self-injurious, obsessive compulsive and autistic features. SMD has evaluated over 120 individuals with SLOS in a natural history trial. This is the largest SLOS cohort of well phenotyped SLOS patients in the country. Previous therapeutic trials evaluated the short-term efficacy of dietary cholesterol supplementation and simvastatin. This work has been supported by the RSH/SLOS Foundation. Niemann-Pick disease type C is a lysosomal disease caused by impaired intracellular cholesterol transport. NPC can be caused by mutation of either NPC1 or NPC2, and its incidence is on the order of 1/100,000. This is a lethal neurodegenerative disorder characterized by progressive cerebellar dysfunction and dementia. While most of the patients are children, the participants range in age from infants to adults. SMD has enrolled approximately 140 individuals in our ongoing, longitudinal natural history/observational trial. This clinical protocol provides for deep phenotyping and biomaterial collection. Previous therapeutic trials evaluated safety and efficacy of n-acetyl cysteine and vorinostat. Current therapeutic trials are evaluating the efficacy of intrathecal 2-hydroxy--cyclodextrin and combined intrathecal/intravenous 2-hydroxy--cyclodextrin. Recent efforts have been focused on newborn screening and exploring opportunities for future therapeutic trials. This work has been supported and facilitated by collaboration with the Ara Parseghian Medical Research Foundation, National Niemann-Pick Disease Foundation, SOAR-NPC and Firefly Fund. CLN3-disease, or juvenile Batten disease, is a recessive lysosomal disease characterized by progressive blindness, seizures, dementia, and behavioral issues. CLN3-disease is due to mutations of CLN3, a gene that encodes a protein of unknown function. SMD has initiated a longitudinal natural history trial which includes deep phenotyping and biomaterial collection for biomarker identification. SMD is working with Amicus Therapeutics and Beyond Batten Disease Foundation on future therapeutic trials. As part of a NCATS project, SMD is participating in a multicenter natural history trial sponsored by Ultragenyx which is enrolling individuals with Creatine Transported Deficiency (CTD). CTD is an X-linked disorder causing severe cognitive impairment and seizures in affected boys. The immediate goal of this project is to obtain information on clinical outcome measures and biomarkers that could be used in a future therapeutic trial.

该项目支持分子畸形学部分进行的临床科学研究。它与Project HD008988进行的基础/转化科学相辅相成。 它巩固并扩展了HD008824和HD008825。 该项目包括自然史/观察和治疗试验遗传疾病由天生的代谢错误引起的。 自然史/观察性研究包括深层表型和用于生物标志物鉴定和表征的生物材料的收集。目前正在研究的疾病包括Smith-Lemli-Opitz综合征，Niemann-Pick疾病，C型，CLN3疾病（Batten病）和肌酸转运蛋白转运蛋白缺乏症。 我们的目标包括改善临床护理，确定发展治疗干预措施。 Smith-Lemli-Opitz综合征（SLO）是胆固醇合成的天生错误，其发病率是1/50,000。 SLOS是一种常染色体隐性多个先天性异常/认知障碍综合征，其特征是面部畸形，生长迟缓和心脏，肺，脑部胃肠道，生殖器，生殖器，肾脏和肢体的可变结构异常。 DHCR7的突变，该酶的基因将7-脱氢胆固醇转化为胆固醇的基因。具有SLOS的个人表现出可变的认知障碍，从轻度学习困难到严重的心理功能障碍。 SLO具有独特的行为表型，其中包括自我伤害，强迫性强迫和自闭症特征。 在一项自然历史试验中，SMD评估了120多名SLO的人。这是该国最大的表型SLOS患者的最大的SLOS队列。 先前的治疗试验评估了饮食胆固醇补充剂和辛伐他汀的短期疗效。 这项工作得到了RSH/SLOS基金会的支持。 Niemann-Pick疾病C型是由细胞内胆固醇转运受损引起的溶酶体疾病。 NPC可能是由NPC1或NPC2的突变引起的，其发病率在1/100,000。 这是一种致命的神经退行性疾病，其特征是进行性小脑功能障碍和痴呆症。虽然大多数患者是儿童，但参与者的年龄从婴儿到成人。 SMD已在我们正在进行的纵向自然历史/观察试验中招募了大约140个人。 该临床方案提供了深层的表型和生物材料收集。 先前的治疗试验评估了N-乙酰基半胱氨酸和伏诺替纳斯特的安全性和功效。当前的治疗试验正在评估鞘内2-羟基 - 环糊精和鞘内/静脉注射2-羟基 - cyclodextrin的疗效。 最近的努力集中在新生儿筛查和探索未来治疗试验的机会上。 这项工作得到了与ARA Parseghian医学研究基金会，国家Niemann-Pick Disease Foundation，Soar-NPC和Firefly Fund的合作的支持和促进。 CLN3-疾病或青少年骨质疾病是一种隐性溶酶体疾病，其特征是进行性失明，癫痫发作，痴呆症和行为问题。 CLN3-酶酶是由于CLN3的突变引起的，该基因编码了功能未知的蛋白质。 SMD启动了一项纵向自然历史试验，其中包括深层表型和生物材料收集，用于生物标志物鉴定。 SMD正在与Amicus Therapeutics和Bever Batten Disease Foundation一起在未来的治疗试验上合作。 作为NCATS项目的一部分，SMD参加了由Ultragenyx赞助的多中心自然历史试验，该试验正在注册患有肌酸运输缺陷（CTD）的人。 CTD是一种X连锁疾病，导致受影响男孩的严重认知障碍和癫痫发作。 该项目的直接目标是获取有关将来可以在将来的治疗试验中使用的临床结果指标和生物标志物的信息。