Lysosomal Disease Network

溶酶体疾病网络

• 批准号: 10707869
• 负责人: Chester B. Whitley
• 金额: $ 112.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707869
• 关键词: Academic support; Acceleration; Accountability; Advocate; Affect; Age of Onset; Attenuated; Beds; Biochemical; Biometry; Birth; Cardiac; Cardiac Myocytes; Cardiovascular system; Career Choice; Catalogs; Categories; Central Nervous System; Characteristics; Child; Clinical; Clinical Research; Clinical Trials; Cognition; Communities; Consent; Data; Databases; Defect; Development; Diagnosis; Disease; Disease Management; Disease Pathway; Disease Progression; Early Diagnosis; Early Intervention; Enrollment; Enzymes; Fabry Disease; Foundations; Framingham Heart Study; Frequencies; Functional disorder; Funding; Future; Gangliosidoses; Gangliosidosis GM1; Gene Mutation; Genes; Genetic Engineering; Genotype; Glycogen storage disease type II; Glycoproteins; Glycosaminoglycans; Goals; Immune Tolerance; Impaired cognition; Impairment; Incidence; Individual; Industry; Infrastructure; Inheritance Patterns; Inherited; Kidney; Knowledge; Knowledge acquisition; Life; Light; Link; Live Birth; Longitudinal Studies; Lysosomal Storage Diseases; Lysosomes; Magnetic Resonance Imaging; Medical; Metabolic; Methods; Mission; Modality; Molecular; Molecular Genetics; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis IV; Musculoskeletal; Mutation; Natural History; Neonatal Screening; Neurologic Dysfunctions; Newborn Infant; Nurses' Health Study; Organ; Outcome; Outcome Measure; Participant; Pathology; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Persons; Pharmacists; Pharmacotherapy; Phenotype; Productivity; Publications; Quality of life; Recommendation; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Residual state; Resources; Role; Secure; Severities; Site; Smooth Muscle Myocytes; Statistical Models; Stem cell transplant; Surveys; Symptoms; System; Techniques; Testing; Therapeutic; Therapeutic Clinical Trial; Training Support; United States National Institutes of Health; autosome; biomarker development; biomarker identification; career; clinical investigation; clinical outcome measures; clinical trial readiness; design; gene therapy; genetic counselor; improved; improved outcome; information gathering; innovation; interest; lipid metabolism; molecular pathology; neglect; next generation; novel strategies; physically handicapped; programs; prospective; skeletal; study population; targeted treatment; therapeutic development; therapeutic effectiveness; treatment response

The lysosomal disorders (LD) are a group of approximately 70 inherited metabolic conditions resulting from defects in lysosomal function; usually deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. Collectively, LD are not especially rare; estimates suggest that approximately 1:5,000 newborns will be affected with one identified LD. Individually however, each disorder occurs with a much lower frequency. Assuming that 180 individuals per 1 million live births will be affected with an LD, extrapolation incidences range from Gaucher at 25 per 1 million births to 7 per 1 million births for GM1- gangliosidosis; other LD are much rarer still. Most LD are monogenetic disorders caused by a mutation in a single gene and follow an autosomal recessive inheritance pattern, although a few are X-linked recessive. Although each LD results from a unique gene mutation, at the biochemical level they share a common characteristic—the inability to clear metabolic substrate from the lysosome. Presenting symptoms vary widely among the disorders and are modified by age of onset and severity (most LD present as either a severe or attenuated phenotype); beyond categorization as severe or attenuated, a more specific genotype/phenotype correlation has not been feasible. To date, about a dozen or so LD have therapeutic options, but apart from MPS I, which has been shown amenable to stem cell transplant, LD drug therapies are not particularly effective in those conditions with neurologic dysfunction. And while new treatments, be it next generation drug therapy, gene therapy, or other gene editing techniques, are essential to improve outcomes for those affected with LD, early detection is critical in order for a person with an LD to hope for a normal life. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. In the past 9 years of NIH funding, the LDN has accelerated knowledge acquisition in the field—with 95 NCBI cited publications—and furthered the development of therapeutic options. For the next 5 years, the overarching thematic goals of the LDN are: clinical trial readiness, newborn screening, long-term outcomes, and global reach. We will advance these goals through clinical investigation via 5 longitudinal studies focused on elucidation of disease pathology by (a) CRIM status and immune tolerance induction in Pompe disease, (b) cardiac and kidney pathology in Fabry disease, (c) multi-system survey (cardiac, developmental, skeletal, QOL) in the mucopolysaccharidoses, and (d) MRI and biomarker development as outcome measures for the gangliosidoses. The fifth project is a survey study designed to catalog both the odyssey individuals go through before reaching a proper diagnosis and the effectiveness of therapeutics at allowing individuals with lysosomal disease (specifically treated MPS) to live an independent life. Every participant who enrolls in an LDN project is expected to complete the survey studies. Biostatistical analysis assures relevant statistical models for each project.

溶酶体疾病(LD)是一组大约70种遗传性代谢疾病，由 溶酶体功能缺陷；通常缺乏脂类代谢所需的单一酶， 糖蛋白，或粘多糖。总的来说，学习障碍并不是特别罕见；估计表明 大约1：5,000名新生儿将受到一种已确认的LD的影响。然而，就个人而言，每一种障碍 发生的频率要低得多。假设每100万名活产婴儿中将有180人受到 LD，GM1的外推发病率从每100万名新生儿中有25名高歇尔到每100万名新生儿中有7名- 神经节苷脂沉着症；其他LD则更为罕见。大多数LD是由基因突变引起的单基因疾病 单基因，并遵循常染色体隐性遗传模式，尽管少数是X连锁隐性遗传。 虽然每个LD都是由一个独特的基因突变引起的，但在生化水平上，它们有一个共同的 特征--不能从溶酶体中清除代谢底物。出现的症状差异很大 在疾病中，并根据发病年龄和严重程度进行修改(大多数LD表现为严重或 弱化表型)；除严重或弱化外，更具体的基因/表型 关联一直都不可行。到目前为止，大约有十几个LD有治疗选择，但除了 MPS I已被证明可用于干细胞移植，LD药物治疗并不是特别有效 在那些有神经功能障碍的情况下。虽然新的治疗方法，无论是下一代药物疗法， 基因治疗或其他基因编辑技术对于改善LD患者的预后至关重要， 早期发现对于患有LD的人来说至关重要，这样才能希望过上正常的生活。在过去的三十年里， 溶酶体疾病已经成为一些最具创新性的治疗方式的试验台。在过去的9年中 在NIH多年的资助下，LDN加速了该领域的知识获取--NCBI引用了95项 出版物--并促进了治疗选择的发展。在接下来的5年里，最重要的 LDN的主题目标是：临床试验准备情况、新生儿筛查、长期结果和全球 伸手。我们将通过5项纵向研究，通过临床研究来推进这些目标 通过(A)Pompe病的Crim状态和免疫耐受的诱导阐明疾病的病理学，(B) Fabry病的心脏和肾脏病理学，(C)多系统调查(心脏、发育、骨骼、 (D)MRI和生物标记物的发展作为结果指标。 神经节苷脂。第五个项目是一项调查研究，旨在将奥德赛个人经历的 在得到正确的诊断和治疗在允许溶酶体患者的有效性之前 疾病(专门治疗的国会议员)过着独立的生活。注册LDN项目的每个参与者 预计将完成调查研究。生物统计分析确保了每一项的相关统计模型 项目。

项目成果

One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease.

• DOI: 10.1371/journal.pone.0152812
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Najafian B;Tøndel C;Svarstad E;Sokolovkiy A;Smith K;Mauer M
• 通讯作者: Mauer M

Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy.

• DOI: 10.1002/ajmg.a.38717
• 发表时间: 2018-06
• 期刊: American journal of medical genetics. Part A
• 作者: Pizzino A;Whitehead M;Sabet Rasekh P;Murphy J;Helman G;Bloom M;Evans SH;Murnick JG;Conry J;Taft RJ;Simons C;Vanderver A;Adang LA
• 通讯作者: Adang LA

Immune Tolerance Strategies in Siblings with Infantile Pompe Disease-Advantages for a Preemptive Approach to High-Sustained Antibody Titers.

• DOI: 10.1016/j.ymgmr.2015.05.004
• 发表时间: 2015-09-01
• 期刊: MOLECULAR GENETICS AND METABOLISM REPORTS
• 影响因子: 1.9
• 作者: Stenger, Elizabeth O;Kazi, Zoheb;Lisi, Emily;Gambello, Michael J;Kishnani, Priya
• 通讯作者: Kishnani, Priya

Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI.

• DOI: 10.3233/prm-140285
• 发表时间: 2014
• 期刊: Journal of pediatric rehabilitation medicine
• 影响因子: 1.9
• 作者: Stevenson DA;Rudser K;Kunin-Batson A;Fung EB;Viskochil D;Shapiro E;Orchard PJ;Whitley CB;Polgreen LE
• 通讯作者: Polgreen LE

Neurology of inherited glycosylation disorders.

• DOI: 10.1016/s1474-4422(12)70040-6
• 发表时间: 2012-05
• 期刊: The Lancet. Neurology
• 作者: Freeze HH;Eklund EA;Ng BG;Patterson MC
• 通讯作者: Patterson MC