Jon J Brudvig, Vicki J Swier, Tyler B Johnson, Jacob C Cain, Melissa Pratt, Mitch Rechtzigel, Hannah Leppert, An N Dang Do, Forbes D Porter, Jill M Weimer
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We further validate biomarker candidates with a retrospective analysis of plasma and CSF samples collected from participants in a natural history study. Plasma samples were evaluated from 22 phenotyped individuals with CLN3 disease, 15 heterozygous carriers, and 6 non-affected non-carriers (NANC).</p><p><strong>Results: </strong>CLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found in <i>CLN3</i> pig CSF and <i>Cln3</i> mouse serum. In plasma samples from individuals with CLN3 disease, glycerophosphoethanolamine and glycerophosphoinositol were significantly elevated with glycerophosphoinositol exhibiting the clearest separation (mean 0.1338 vs 0.04401 nmol/mL for non-affected non-carriers). Glycerophosphoinositol demonstrated excellent sensitivity and specificity as a biomarker, with a receiver operating characteristic area under the curve of 0.9848 (<i>P</i> = .0003).</p><p><strong>Conclusions: </strong>GPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":null,"pages":null},"PeriodicalIF":3.4000,"publicationDate":"2022-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c2/f3/10.1177_11772719221107765.PMC9535353.pdf","citationCount":"3","resultStr":"{\"title\":\"Glycerophosphoinositol is Elevated in Blood Samples From <i>CLN3</i> <sup>Δex7-8</sup> pigs, <i>Cln3</i> <sup>Δex7-8</sup> Mice, and CLN3-Affected Individuals.\",\"authors\":\"Jon J Brudvig, Vicki J Swier, Tyler B Johnson, Jacob C Cain, Melissa Pratt, Mitch Rechtzigel, Hannah Leppert, An N Dang Do, Forbes D Porter, Jill M Weimer\",\"doi\":\"10.1177/11772719221107765\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants in <i>CLN3.</i> Despite decades of intense research, specific biofluid biomarkers of disease status have not been reported, hindering clinical development of therapies. Thus, we sought to determine whether individuals with CLN3 Batten disease have elevated levels of specific metabolites in blood.</p><p><strong>Methods: </strong>We performed an exhaustive metabolomic screen using serum samples from a novel minipig model of CLN3 Batten disease and validated findings in <i>CLN3</i> pig serum and CSF and <i>Cln3</i> mouse serum. We further validate biomarker candidates with a retrospective analysis of plasma and CSF samples collected from participants in a natural history study. Plasma samples were evaluated from 22 phenotyped individuals with CLN3 disease, 15 heterozygous carriers, and 6 non-affected non-carriers (NANC).</p><p><strong>Results: </strong>CLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found in <i>CLN3</i> pig CSF and <i>Cln3</i> mouse serum. In plasma samples from individuals with CLN3 disease, glycerophosphoethanolamine and glycerophosphoinositol were significantly elevated with glycerophosphoinositol exhibiting the clearest separation (mean 0.1338 vs 0.04401 nmol/mL for non-affected non-carriers). Glycerophosphoinositol demonstrated excellent sensitivity and specificity as a biomarker, with a receiver operating characteristic area under the curve of 0.9848 (<i>P</i> = .0003).</p><p><strong>Conclusions: </strong>GPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. 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引用次数: 3
摘要
介绍:CLN3巴顿病是一种罕见的小儿神经退行性溶酶体疾病，由CLN3双等位基因疾病相关变异引起。尽管经过数十年的深入研究，疾病状态的特异性生物流体生物标志物尚未报道，这阻碍了临床治疗的发展。因此，我们试图确定患有CLN3巴顿病的个体是否具有血液中特定代谢物水平升高。方法:我们使用一种新型CLN3巴滕病迷你猪模型的血清样本进行了详尽的代谢组学筛选，并验证了CLN3猪血清和CSF以及CLN3小鼠血清中的发现。我们通过对自然历史研究参与者的血浆和脑脊液样本进行回顾性分析，进一步验证候选生物标志物。对22名表型型CLN3疾病患者、15名杂合携带者和6名未受影响的非携带者(NANC)的血浆样本进行了评估。结果:4个年龄段的CLN3猪血清样本中，甘油磷酸肌醇(GPI)、甘油磷酸乙醇胺(GPE)、甘油磷酸胆碱(GPC)和甘油磷酸丝氨酸(GPS) 4种甘油磷酸二酯含量均显著升高。GPI和GPE的升高幅度最大，CLN3猪CSF和CLN3小鼠血清中GPI和GPE的升高幅度相似。在CLN3疾病患者的血浆样本中，甘油磷酸乙醇胺和甘油磷酸肌醇显著升高，其中甘油磷酸肌醇分离最明显(未受影响的非携带者平均为0.1338 vs 0.04401 nmol/mL)。甘油磷酸肌醇作为生物标志物具有良好的敏感性和特异性，曲线下的受试者工作特征面积为0.9848 (P = 0.0003)。结论:GPE和GPI可作为CLN3疾病状态的生物标志物。特别是，GPI在不同的CLN3患者队列中显示一致的升高。这提高了使用这些生物标志物作为基于血液的诊断测试或作为疾病改善治疗的疗效测量的潜力。
Glycerophosphoinositol is Elevated in Blood Samples From CLN3Δex7-8 pigs, Cln3Δex7-8 Mice, and CLN3-Affected Individuals.
Introduction: CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants in CLN3. Despite decades of intense research, specific biofluid biomarkers of disease status have not been reported, hindering clinical development of therapies. Thus, we sought to determine whether individuals with CLN3 Batten disease have elevated levels of specific metabolites in blood.
Methods: We performed an exhaustive metabolomic screen using serum samples from a novel minipig model of CLN3 Batten disease and validated findings in CLN3 pig serum and CSF and Cln3 mouse serum. We further validate biomarker candidates with a retrospective analysis of plasma and CSF samples collected from participants in a natural history study. Plasma samples were evaluated from 22 phenotyped individuals with CLN3 disease, 15 heterozygous carriers, and 6 non-affected non-carriers (NANC).
Results: CLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found in CLN3 pig CSF and Cln3 mouse serum. In plasma samples from individuals with CLN3 disease, glycerophosphoethanolamine and glycerophosphoinositol were significantly elevated with glycerophosphoinositol exhibiting the clearest separation (mean 0.1338 vs 0.04401 nmol/mL for non-affected non-carriers). Glycerophosphoinositol demonstrated excellent sensitivity and specificity as a biomarker, with a receiver operating characteristic area under the curve of 0.9848 (P = .0003).
Conclusions: GPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies.
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