Project 2: GeorgiaCenter for the Investigation of Factor VIII Inhibitors and Glycosylation

项目 2：乔治亚因子 VIII 抑制剂和糖基化研究中心

• 批准号: 10406320
• 负责人: Li Lei
• 金额: $ 30.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406320
• 关键词: Affect; Amino Acids; Antibodies; Attention; B-Lymphocytes; Birth; Blood Coagulation Disorders; Carbohydrates; Cells; Clinical; Clinical Treatment; Coagulants; Coagulation Process; Complex; Development; Diagnosis; Environment; Epitopes; F8 gene; Factor V; Factor VIII; Functional disorder; Glycopeptides; Glycoproteins; Health Care Costs; Hemophilia A; Immune Tolerance; Immune system; Immunoglobulin G; Immunoglobulins; Intravenous; Investigation; Link; Measurement; Medicine; Modification; Morbidity - disease rate; Patient Monitoring; Patients; Pattern; Perception; Plasma; Property; Protein Glycosylation; Proteins; Recombinants; Replacement Therapy; Reporting; Research; Risk; Sampling; Surrogate Markers; Surveys; T-Lymphocyte; Testing; Translations; Variant; base; de novo mutation; glycosylation; immunogenic; immunogenicity; inhibitor; innovation; male; neutralizing antibody; novel; protein aggregation; tool

Summary Congenital Hemophilia A (HA) is an X-linked bleeding disorder due to a lack or dysfunction of coagulation FVIII (FVIII). Nearly 1 in 5,000 live male births are diagnosed with HA with 40% of whom involving of sporadic cases caused by de novo mutations. Plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) are two major intravenous replacement therapy medicines for HA treatment. FVIII neutralizing antibodies, or inhibitors, occur in 25-30% of severe HA patients receiving protein replacement. These FVIII inhibitors essentially abolish the efficacy of the coagulant treatment, resulting in a considerable increase in the morbidity and healthcare cost. Although both rFVIII and pdFVIII share similar to identical primary amino acids, the risk of FVIII antibodies in previously untreated patients (PUPs) was reported to be higher following rFVIII treatment. As a glycoprotein, pdFVIII and rFVIII are different in glycosylation, a post-translation modification (PTM) that is capable of alter the immunogenicity of protein Therefore, in this project, we will develop a set of novel glycoanalysis toolset for FVIII inhibitors. In order to investigate the effect of the host glyco environment on FVIII, we propose to use FVIII closely associated VWF and FV as surrogate marker to show to potential effect on FVIII glycosylation in HA patients who developed FVIII inhibitors. Also, based on our developed MS-based approach, glycosylation pattern of total immunoglobulins, specific FVIII inhibitors, FV, VWF, and overall glycome changes of the host cell environment will be thoroughly characterized in a large number of HA patients’ samples, close attention to those undergone immune tolerance induction (ITI). The overall results obtained from this project will be significant for understanding the fundamental mechanism of FVIII immunogenicity.

总结