Leveraging modulation of polyamine metabolism for therapeutic advantage in genetic disorders

摘要 我们处于研究与多胺相关的新型神经发育障碍的前沿。我们的 最重要的假设是，多胺途径基因的突变导致病理失衡。 导致神经发育障碍的受影响个体的多胺特征。具体来说，巴赫曼- Bupp综合征(BABS)是一种常染色体显性遗传病，由杂合子新变异体引起 在鸟氨酸脱羧酶1(ODC1)基因中，Snyder-Robinson综合征(SRS)是X连锁基因 精胺合成酶(SMS)基因突变引起的疾病。ODC1和短信都是前哨 调节多胺代谢的基因。然而，将多胺与这些物质联系起来的确切途径 神经发育障碍的定义并不明确。基于我们初步的体外、动物和临床实验 患者数据，我们假设失调的多胺(腐胺、亚精胺、精胺)可能是 正常，BABS和SRS表型可以通过药物干预逆转。 重要的是，我们有令人信服的数据表明，BABS患者积累了活性的ODC酶和 产生大量腐胺，我们发现FDA批准的ODC抑制剂DFMO (依氟鸟氨酸)显著改善BABS患者的症状。我们进一步假设，类似的收益- 其他多胺基因的功能(GOF)或功能丧失(LOF)变体(例如eIF5A、DHPS、DOHH、SMOX， AZ，AZI)的存在，有可能引起未知的多胺疾病。不幸的是，人们对此知之甚少 关于控制多胺相关神经发育表型的潜在机制 精神错乱。鉴于这些事实，这项应用的总体目标是解开分子机制 以及将多胺连接到BABS和SRs并测试多胺靶向剂(DFMO， Me2Spm等)在转基因BABS和SRS小鼠模型和人类患者来源的原代细胞中 淋巴母细胞系。以下是为实现这些目标而设计的具体目标。目标1：确定特征 并从药物上治疗模仿个体ODC1功能获得突变的遗传小鼠模型 与BABS一起询问控制人类BABS患者表型的分子机制。目标2： 在受SRS影响的个体细胞和一种新的遗传小鼠模型中优化药物治疗 这模仿了SRS患者的一种常见突变。目的3：扩大对BABS和SRS的临床认识 以改善对越来越多的罕见疾病的临床护理。因为这项提议的主要目的是 确定控制BABS和SRS的分子机制和代谢途径，以及测试 在相关模型中治疗的有效性，关键是我们使用特定于障碍的小鼠模型。我们会 正如我们之前发表的那样，使用我们的BABS和SRS小鼠模型和患者来源的细胞系来 确定多胺抑制剂治疗的体内效果。我们的研究提供了难得的机会 有可能治愈或至少改善BABS和SRS的症状，这是两种人类遗传病。

ABSTRACT We are at the forefront of investigating novel neurodevelopmental disorders associated with polyamines. Our overarching hypothesis is that mutations in genes of the polyamine pathway result in pathologically unbalanced polyamine profiles in affected individuals that lead to neurodevelopmental disorders. Specifically, Bachmann- Bupp Syndrome (BABS) is an autosomal dominant genetic disorder caused by heterozygous de novo variants in the ornithine decarboxylase 1 (ODC1) gene, and Snyder-Robinson Syndrome (SRS) is an X-linked genetic disorder that results from mutations in the spermine synthase (SMS) gene. Both ODC1 and SMS are sentinel genes in the regulation of polyamine metabolism. However, the precise pathways linking polyamines to these neurodevelopmental disorders are not well defined. Based on our preliminary in vitro, animal, and clinical patient data, we hypothesize that dysregulated polyamines (putrescine, spermidine, spermine) can be normalized, and BABS and SRS phenotypes can be reversed through pharmacological intervention. Importantly, we have compelling data showing that BABS patients accumulate active ODC enzyme and produce large amounts of putrescine, and we showed that the FDA-approved ODC inhibitor DFMO (Eflornithine) significantly improves BABS patient symptoms. We further hypothesize that similar gain-of- function (GOF) or loss-of-function (LOF) variants in other polyamine genes (e.g., eIF5A, DHPS, DOHH, SMOX, AZ, AZI) exist, potentially giving rise to yet unknown polyamine disorders. Unfortunately, very little is known about the underlying mechanisms that govern the phenotypes of polyamine-linked neurodevelopmental disorders. In light of these facts, the overall goals of this application are to unravel the molecular mechanisms and metabolic pathways that link polyamines to BABS and SRS and test polyamine-targeting agents (DFMO, Me2Spm, others) in transgenic BABS and SRS murine models and human patient-derived primary cells and lymphoblastoid cell lines. The following Specific Aims are designed to pursue these goals. Aim 1: Characterize and pharmacologically treat genetic mouse models that mimic ODC1 gain-of-function mutations of individuals with BABS to interrogate the molecular mechanisms that govern the human BABS patient phenotype. Aim 2: Optimize pharmacologic treatment in cells from SRS-affected individuals and in a novel genetic mouse model that mimics a common mutation in SRS patients. Aim 3: Expand the clinical understanding of BABS and SRS to improve clinical care of a growing family of rare diseases. As the primary purpose of this proposal is to define molecular mechanisms and metabolic pathways that govern BABS and SRS as well as to test the effectiveness of treatments in relevant models, it is critical that we use disorder-specific mouse models. We will use our BABS and SRS murine models and patient-derived cell lines, as we have previously published, to determine the in vivo effectiveness of polyamine inhibitor treatments. Our study provides the rare opportunity to potentially cure or at least ameliorate the symptoms of BABS and SRS, two human genetic disorders.