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: 10705139
• 负责人: JULIE D SABA
• 金额: $ 20.19万
• 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/10705139
• 关键词: Adaptive Immune System; Addison' s disease; Adrenal gland hypofunction; Adult; Affect; Age; Age Years; Antibodies; Anticoagulation; 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 Clinical Trials; 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; Innate Immune System; Kidney; Kidney Transplantation; Knockout Mice; Laboratories; Leukocytes; Lipids; Lymphocyte; Lymphocyte Count; Lymphocyte Subset; Lymphopenia; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular Chaperones; Monitor; Monitoring Clinical Trials; Mutation; Natural Killer Cells; Neurologic; Operative Surgical Procedures; Organ; Patients; Pediatric cohort; Peripheral Blood Mononuclear Cell; Phosphorylation; Physicians; Physiological Processes; Plasma; Population; Primary Hyperoxaluria; Proteins; Pyridoxal Phosphate; Reference Values; Regulatory T-Lymphocyte; Renal function; Reporting; Rest; Role; Safety; Sampling; Severities; 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; pharmacologic; primary endpoint; response; safety testing; sphingosine 1-phosphate; sphingosine phosphate lyase insufficiency syndrome; 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是一种遗传性代谢性儿童综合征 由SGPL 1的隐性突变引起。受影响的儿童表现出类固醇耐药性肾病综合征， 快速进展为终末期肾病、肾上腺功能不全、神经缺陷和淋巴细胞减少症。一 已经观察到一系列严重程度，其中最严重的受影响患者在子宫内死亡，而其他人则存活 直到成年，尽管需要透析或肾移植。重要的是，SPLIS没有特效药， 因此迫切需要开发新的安全有效的治疗方法。SGPL 1编码 磷酸鞘氨醇裂解酶（SPL），一种负责不可逆的细胞内酶， 在鞘脂代谢的最后一步，1-磷酸鞘氨醇（S1 P）被分解。S1 P是一种生物活性 通过其5个G蛋白偶联的S1 P受体发出信号以调节淋巴细胞运输和其他 生理过程。SGPL 1突变损害SPL活性并导致鞘脂蓄积， 器官功能障碍和衰竭。此外，SPLIS儿童中异常的S1 P信号传导导致淋巴细胞减少， 淋巴细胞出口缺陷SPL活性依赖于维生素B6作为辅助因子。独立于其作为 作为超过160种酶促反应中的辅酶，维生素B6也可以作为伴侣，稳定维生素B6。 B6依赖酶。以维生素B6维生素吡哆醇形式存在的维生素B6的药理学剂量具有 被证明对涉及B6依赖酶的先天性代谢缺陷有效。基于鼓励 在两名接受维生素B6补充治疗的SPLIS患者中的初步发现，我们正准备 评估维生素B6补充剂作为SPLIS的第一种特异性治疗的安全性和有效性。 开发用于监测SPLIS患者血液样本中SPL活性的可靠检测方法的挑战 使依赖疾病生物标志物成为SPLIS中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S1 P水平将作为反映SPLIS的可靠生物标志物 疾病状态。不幸的是，血浆S1 P和其他主要鞘脂的儿科参考范围 至今未被报道。此外，还没有研究全面地分析了免疫系统中的循环免疫细胞群。 苏人解已被报告。为了证实我们的假设并克服这些障碍推进治疗 对于患有SPLIS和其他鞘脂代谢紊乱的儿童，我们将描述主要的血浆 SPLIS患儿和健康儿童及青少年免疫功能的鞘脂和血液标志物 成人对照组。在实现我们的特定目标时，我们将验证血浆S1 P和ALC作为稳健的SPLIS 疾病生物标志物。我们将建立一套全面的血浆鞘脂的参考范围， 健康的儿科和年轻的成年人队列，这将是有用的，在未来的诊断，监测和 在广泛的鞘脂疾病中进行临床试验。我们的研究结果将特别促进临床 试验准备测试维生素B6辅因子补充剂治疗SPLIS的安全性和有效性。