Investigations of Methylmalonic Acidemia and Related Disorders

甲基丙二酸血症及相关疾病的调查

• 批准号: 9572262
• 负责人: Charles P Venditti
• 金额: $ 142.42万
• 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/9572262
• 关键词: Acyl Coenzyme A; Adult; Affect; Animal Model; Basal Ganglia; Biochemistry; Carbon; Cardiac; Cardiomyopathies; Childhood; Chronic Kidney Failure; Clinic; Clinical; Clinical Protocols; Clinical Research; Cobalamin; Collaborations; Complex; Cultured Cells; Databases; Development; Developmental Delay Disorders; Diabetes Mellitus; Disease; Effectiveness; End stage renal failure; Enzymes; Family member; Functional disorder; Gene Expression; Generations; Genomic approach; Genomics; Goals; Growth; Heterozygote; Hospitals; Human; Impairment; Inborn Errors of Metabolism; Individual; Inherited; Intellectual Property; Investigation; Knockout Mice; Laboratories; Legal patent; Lipids; Manuscripts; Medical; Metabolic; Metabolic Diseases; Metabolism; Methylmalonyl-CoA Mutase; Modeling; Mus; Mutant Strains Mice; Mutase; Myocardial dysfunction; NPC1 gene; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Natural History; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteoporosis; Outcome; Pancreas; Pancreatitis; Paper; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Primary carcinoma of the liver cells; Proteomics; Protocols documentation; Published Comment; Risk Factors; Severity of illness; Skeletal Muscle; Stroke; Supraoptic Vertical Ophthalmoplegia; Syndrome; Testing; Textbooks; Therapeutic Intervention; Transgenes; United States National Institutes of Health; Validation; Viral; Viral Genes; Visit; Vitamin B 12; Vitamin B 12 Deficiency; Work; Zebrafish; adeno-associated viral vector; amino acid metabolism; blood glucose regulation; clinical phenotype; cohort; experimental study; gene therapy; genetic approach; genome editing; genotoxicity; glucose tolerance; insight; insulin sensitivity; ketotic hyperglycinemia; metabolic phenotype; metabolomics; methylmalonic aciduria; methylmalonyl coA mutase deficiency; microbiome; mouse model; novel therapeutics; protein biomarkers; screening; stable isotope; success; targeted treatment; translational research program

We study a group of related inborn errors of metabolism, the hereditary methylmalonic acidemias (MMA), disorders of intracellular cobalamin metabolism and propionic acidemia (PA), in the clinic and laboratory. Affected patients are medically fragile and suffer from multisystemic complications such as severe metabolic instability, stroke of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, cardiomyopathy and developmental delay. Despite intensive study since the early 1960s, few patients with MMA or PA have survived into adulthood and evidence for effectiveness of current medical therapies is lacking, a fact that stands in stark contrast to the practice of screening all US newborns for these disorders. Because patients with MMA and PA display pathology that can be seen in many common conditions, such as vitamin B12 deficiency, stroke syndromes, pancreatic dysfunction, diabetes, chronic kidney disease, osteoporosis, cardiac dysfunction and obesity, it is likely that the careful elucidation of patient phenotypes will provide new insights into the pathophysiology of more complex and prevalent disorders, and perhaps, suggest new pathways to target for therapeutic intervention that could affect millions of patients. The translational research program has three major interrelated goals. Goal 1 is to define the natural history of the conditions using clinical research; Goal 2 is to investigate the disorders in the laboratory using metabolic, genetic and genomic approaches, including animal modeling and Goal 3 is to develop new treatments for the disorders, focusing gene therapy strategies. The clinical characterization of patients with methylmalonic acidemia (MMA) and related disorders, via a dedicated natural history study, NHGRI protocol Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders (ClinicalTrials.gov Identifier: NCT00078078) has continued. Through our clinical protocol, we have continued to accrue patients with MMA and cobalamin metabolic disorders and have evaluated > 190 affected individuals; this is the largest single center cohort of such patients in the world. A new endeavor to study propionic acidemia has been initiated this past year via NHGRI protocol Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia (ClinicalTrials.gov Identifier:NCT02890342). Like the methylmalonic acidemia (MMA) protocol, this clinical effort is unique in that it is the only dedicated natural history study being conducted on PA that utilizes an intensive dedicated hospital visit to perform detailed clinical phenotyping. At present, 10 patients have been evaluated and another 10 are expected before the end of 2017. We have continued to focus on the clinical characterization of patients to expand our understanding of these disorders. We have written a number of contemporary reviews (1-3) and opinions (4) on management of MMA and PA as well as chapters for the major pediatric textbooks on vitamin B12, organic acidemias, one carbon metabolism (reference 5-6) and amino acid metabolism (references 7-13). Active efforts include defining the metabolic phenotype of MMA and PA patients with stable isotopes; the construction of an integrated clinical outcomes database for MMA and PA; the analysis of cardiac phenotypes (in collaboration with NHLBI colleagues); and the identification and validation of protein biomarkers that correlate with disease severity. Translational investigations have continued to focus on experiments that use -omic approaches to define disease mechanisms as well as the generation and characterization of animal models. One recent paper (reference 14) describes a comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity. We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. We found that MUT heterozygosity might be a risk factor to develop T2D in humans. These experiments were performed in collaboration with Dr Patti from Harvard. We continue to characterize knock-out mouse models of MMAA deficiency, which causes a relatively common and severe form of vitamin B12 responsive MMA, combined malonic-methylmalonic acidemia (CMAMMA) due to acyl-coA synthase family member 3 (ACSF3) deficiency, and cobalamin C deficiency (MMACHC). In the next year, we will continue to characterize the mutant mice using genomic, proteomic and metabolomic analyses, then test new therapeutics, such as gene therapy. We have also initiated a parallel effort to model lethal metabolic disorder such as MUT MMA and cblC deficiency with zebrafish. We have continued to study gene therapy as treatment for methylmalonyl-CoA mutase (MUT) deficiency, the most common and severe form of MMA. We have written general reviews on gene therapy for inborn errors of metabolism (reference 15) and the use of genome editing in the treatment of IEMs (reference 16). In collaboration with Dr Shawn Burgess of the NHGRI IRP, we had previously defined the genotoxicity of adeno-associated viral (AAV) gene therapy in mice. The controversy surrounding AAV and hepatocellular carcinoma (HCC) has expanded, and we have contributed an important commentary on this topic (reference 17). Moving forward, we plan to refine our efforts to develop an AAV vector for MUT MMA that can be safely administered to patients. As well, our efforts to implement AAV gene therapy for MUT type MMA continue to progress. We have developed new AAV vectors for MUT MMA, garnered intellectual property, and licensed our transgenes for commercial development. We have also created AAV gene therapies for cobalamin C deficiency and Niemann-Pick Type C (NPC) disease (with Dr William Pavan of the NHGRI), setting the stage for the development of gene therapy for several disorders within the NIH IRP. Manuscripts detailing our success in developing AAV gene therapy for NPC1 disease (reference 18) and a recent patent related to this work (reference 19) were also achieved in the last year.

我们研究了一组相关的先天性代谢错误，遗传性甲基丙二酸血症（MMA），细胞内钴胺素代谢紊乱和丙酸血症（PA），在临床和实验室。受影响的患者在医学上是脆弱的，并遭受多系统并发症，如严重的代谢不稳定，基底神经节中风，胰腺炎，终末期肾功能衰竭，生长障碍，骨质疏松症，心肌病和发育迟缓。尽管自20世纪60年代初以来进行了深入的研究，但很少有MMA或PA患者存活到成年，而且目前缺乏有效的医学治疗证据，这一事实与对所有美国新生儿进行这些疾病筛查的做法形成鲜明对比。由于MMA和PA患者的病理表现可以在许多常见情况下看到，如维生素B12缺乏症、中风综合征、胰腺功能障碍、糖尿病、慢性肾病、骨质疏松症、心功能障碍和肥胖，因此对患者表型的仔细阐明可能会为更复杂和普遍疾病的病理生理学提供新的见解。为可能影响数百万患者的治疗干预提出新的途径。