Validating absolute lymphocyte count and plasma sphingosine-1-phosphate as disease biomarkers of sphingosine phosphate lyase insufficiency syndrome in anticipation of a pyridoxine clinical trial

验证绝对淋巴细胞计数和血浆 1-磷酸鞘氨醇作为磷酸鞘氨醇裂解酶不足综合征的疾病生物标志物，以期待吡哆醇临床试验

• 批准号: 10515118
• 负责人: JULIE D SABA
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515118
• 关键词: Adaptive Immune System; Addison' s disease; Adrenal gland hypofunction; Adult; Affect; Age; Age-Years; Antibodies; Biochemical Reaction; Biological Assay; Biological Markers; Blood; Blood specimen; CD8B1 gene; Cells; Ceramides; Child; Childhood; Clinical Trials; Coenzyme A; Color; Complete Blood Count; Conduct Clinical Trials; Coupled; Cytometry; Defect; Dendritic Cells; Dependovirus; Development; Diagnosis; Dialysis procedure; Disease; Dose; Emigrant; End stage renal failure; Enzymes; Exhibits; Failure; Female; Fibroblasts; Freezing; Functional disorder; Future; GTP-Binding Proteins; Gender; Immune; Immune System Diseases; Immunologic Markers; Impairment; In Vitro; Inborn Errors of Metabolism; Individual; Inflammation; Inherited; Kidney; Kidney Transplantation; Knockout Mice; Laboratories; Leukocytes; Lipids; Lymphocyte; Lymphocyte Count; Lymphocyte Subset; Lymphopenia; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular Chaperones; Monitor; Mutation; Natural Killer Cells; Neurologic; Operative Surgical Procedures; Organ; Patient Monitoring; Patients; Pediatric cohort; Peripheral Blood Mononuclear Cell; Pharmacology; Physicians; Physiological Processes; Plasma; Population; Primary Hyperoxaluria; Proteins; Pyridoxal Phosphate; Reference Values; Regulatory T-Lymphocyte; Renal function; Reporting; Rest; Role; Safety; Sampling; Severities; Ships; Signal Transduction; Sphinganine-1-phosphate aldolase; Sphingolipids; Sphingosine-1-Phosphate Receptor; Steroid-resistant idiopathic nephrotic syndrome; Supplementation; Syndrome; T-Lymphocyte; Thymus Gland; Time; Vascular Permeabilities; Vitamin B6; Whole Blood; angiogenesis; base; clinical trial readiness; cofactor; cohort; effective therapy; enzyme activity; gene therapy; immune function; in utero; instrument; liquid chromatography mass spectrometry; lymphocyte trafficking; male; monocyte; mouse model; mutant; neutrophil; novel; primary endpoint; response; safety testing; sphingosine 1-phosphate; targeted treatment; young adult

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is an inherited metabolic childhood syndrome caused by recessive mutations in SGPL1. Affected children exhibit steroid-resistant nephrotic syndrome with rapid progression to end stage renal disease, adrenal insufficiency, neurological defects and lymphopenia. A range of severity has been observed, with the most severely affected patients dying in utero, while others live to adulthood, albeit requiring dialysis or kidney transplantation. Importantly, there is no specific cure for SPLIS, and thus there is a dire need for the development of novel safe and effective treatments. SGPL1 encodes sphingosine phosphate lyase (SPL), an essential intracellular enzyme responsible for the irreversible breakdown of sphingosine-1-phosphate (S1P) in the final step of sphingolipid metabolism. S1P is a bioactive lipid that signals through its five G protein coupled S1P receptors to regulate lymphocyte trafficking and other physiological processes. SGPL1 mutations impair SPL activity and cause sphingolipid accumulation leading to organ dysfunction and failure. In addition, aberrant S1P signaling in SPLIS children leads to lymphopenia due to a defect in lymphocyte egress. SPL activity depends on vitamin B6 as a cofactor. Independent of its role as a coenzyme in over 160 enzymatic reactions, vitamin B6 can also function as a chaperone, stabilizing vitamin B6-dependent enzymes. Pharmacological doses of vitamin B6 in the form of the B6 vitamer pyridoxine have proven effective in inborn errors of metabolism involving B6-dependent enzymes. Based on encouraging preliminary findings in two SPLIS patients treated with vitamin B6 supplementation, we are preparing to evaluate the safety and efficacy of vitamin B6 supplementation as the first specific treatment for SPLIS. Challenges to developing a reliable assay for monitoring SPL activity in blood samples from SPLIS patients make reliance on disease biomarkers a critical component of any clinical trial in SPLIS. We hypothesize that absolute lymphocyte count (ALC) and plasma S1P levels will serve as reliable biomarkers that reflect SPLIS disease status. Unfortunately, pediatric reference ranges for plasma S1P and other major sphingolipids have not been reported to date. Further, no study comprehensively profiling circulating immune cell populations in SPLIS has been reported. To confirm our hypothesis and overcome these obstacles to advancing treatments for children with SPLIS and other sphingolipid metabolic disorders, we will characterize the major plasma sphingolipids and blood markers of immune function in children with SPLIS and a healthy pediatric and young adult control cohort. In accomplishing our Specific Aims, we will validate plasma S1P and ALC as robust SPLIS disease biomarkers. We will establish reference ranges for a comprehensive set of plasma sphingolipids in a healthy pediatric and young adult cohort that will be useful in the future for diagnosis, monitoring and conducting clinical trials in a broad range of sphingolipid disorders. Our results will specifically facilitate clinical trial readiness for testing the safety and efficacy of vitamin B6 cofactor supplementation to treat SPLIS.

磷酸鞘氨醇裂解酶不足综合征 (SPLIS) 是一种遗传性代谢儿童综合征 由 SGPL1 隐性突变引起。受影响的儿童表现出类固醇抵抗性肾病综合征 快速进展为终末期肾病、肾上腺功能不全、神经系统缺陷和淋巴细胞减少。一个 已经观察到严重程度的范围，受影响最严重的患者在子宫内死亡，而其他患者则存活 到成年，尽管需要透析或肾移植。重要的是，SPLIS 没有具体的治疗方法， 因此，迫切需要开发新的安全有效的治疗方法。 SGPL1 编码 磷酸鞘氨醇裂解酶 (SPL)，一种重要的细胞内酶，负责不可逆的裂解 1-磷酸鞘氨醇 (S1P) 在鞘脂代谢的最后一步中分解。 S1P具有生物活性 脂质通过其 5 个 G 蛋白偶联的 S1P 受体发出信号来调节淋巴细胞运输和其他 生理过程。 SGPL1 突变会损害 SPL 活性并导致鞘脂积累，从而导致 器官功能障碍和衰竭。此外，SPLIS 儿童中异常的 S1P 信号传导导致淋巴细胞减少 淋巴细胞排出缺陷。 SPL 活性依赖于维生素 B6 作为辅助因子。独立于其作为 维生素 B6 是 160 多种酶促反应中的辅酶，还可以充当伴侣，稳定维生素 B6 依赖性酶。 B6 维生素 B6 吡哆醇形式的维生素 B6 的药理学剂量为 已证明对涉及 B6 依赖性酶的先天性代谢缺陷有效。基于鼓励 两名接受维生素 B6 补充剂治疗的 SPLIS 患者的初步结果，我们正准备 评估维生素 B6 补充剂作为 SPLIS 首个特异性治疗的安全性和有效性。 开发可靠的检测方法来监测 SPLIS 患者血液样本中的 SPL 活性面临的挑战 使疾病生物标志物成为 SPLIS 任何临床试验的关键组成部分。我们假设 绝对淋巴细胞计数 (ALC) 和血浆 S1P 水平将作为反映 SPLIS 的可靠生物标志物 疾病状况。不幸的是，血浆 S1P 和其他主要鞘脂的儿科参考范围已经 迄今为止尚未被报道。此外，还没有研究全面分析循环免疫细胞群 SPLIS 已被报道。证实我们的假设并克服推进治疗的这些障碍 对于患有 SPLIS 和其他鞘脂代谢紊乱的儿童，我们将表征主要血浆 SPLIS 儿童以及健康儿科和青少年的鞘脂和免疫功能血液标志物 成人对照队列。为了实现我们的具体目标，我们将验证血浆 S1P 和 ALC 是否具有强大的 SPLIS 疾病生物标志物。我们将为一套全面的血浆鞘脂建立参考范围 健康的儿科和年轻人队列将在未来用于诊断、监测和 对广泛的鞘脂疾病进行临床试验。我们的结果将特别促进临床 测试维生素 B6 辅因子补充剂治疗 SPLIS 的安全性和有效性的试验准备。