Leveraging modulation of polyamine metabolism for therapeutic advantage in genetic disorders

利用多胺代谢的调节来获得遗传性疾病的治疗优势

基本信息

批准号：
10564999
负责人：
ANDRE S BACHMANN
金额：
$ 71.62万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564999
关键词：
Adult Affect Aftercare Animal Model Animals Behavioral Biochemical Biochemical Pathway Biochemistry Biological Assay Biology Blood specimen C-terminal CRISPR/Cas technology Cell Line Cells Clinical Clinical Data DL-alpha-Difluoromethylornithine Data Data Analyses Developmental Delay Disorders Diagnosis Disease Disease model Dominant Genetic Conditions Dose Drug Kinetics Effectiveness Eflornithine Enzymes FDA approved Family Gene Mutation Genes Genetic Genetic Diseases Goals Hair Heterozygote Histology Human Human Genetics In Vitro Individual Intervention Lead Light Link Metabolic Metabolic Pathway Metabolism Modeling Molecular Monitor Mus Mutation Neurodevelopmental Disorder Neurology Newborn Infant Ornithine Decarboxylase Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Phenotype Plasma Polyamines Publishing Putrescine Rare Diseases Regulation Sampling Sentinel Skin Snyder-Robinson syndrome Spermidine Spermine Spermine Synthase Symptoms Syndrome Testing The Jackson Laboratory Therapeutic Tissue Sample Tissues Transgenic Organisms Treatment Effectiveness Variant Whole Blood analog autosome behavioral response clinical care de novo mutation design differential expression eIF-5A effectiveness testing gain of function gain of function mutation genetic testing genetic variant genome editing improved in vivo inhibitor loss of function loss of function mutation lymphoblastoid cell line metabolomics mouse model novel novel therapeutics pharmacologic reduce symptoms response screening targeted agent tool transcriptome transcriptomics treatment response

项目摘要

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.

抽象的我们处于研究与多胺相关的新型神经发育障碍的前沿。我们的总体假设是多胺途径基因突变导致病理不平衡受影响个体中的多胺谱会导致神经发育障碍。具体来说，巴赫曼- 布普综合征 (BABS) 是一种由杂合子新生变异引起的常染色体显性遗传病存在于鸟氨酸脱羧酶 1 (ODC1) 基因中，斯奈德-罗宾逊综合征 (SRS) 是一种 X 连锁遗传病由精胺合成酶 (SMS) 基因突变引起的疾病。 ODC1和SMS都是哨兵调节多胺代谢的基因。然而，将多胺与这些物质连接起来的精确途径神经发育障碍尚无明确定义。基于我们的初步体外、动物和临床研究根据患者数据，我们假设失调的多胺（腐胺、亚精胺、精胺）可以正常化，并且 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 患者体内积累了活性 ODC 酶并产生大量的腐胺，我们展示了 FDA 批准的 ODC 抑制剂 DFMO （Eflornithine）可显着改善 BABS 患者的症状。我们进一步假设类似的增益其他多胺基因（例如 eIF5A、DHPS、DOHH、SMOX、 AZ、AZI）的存在，可能会引起未知的多胺疾病。不幸的是，人们知之甚少关于控制多胺相关神经发育表型的潜在机制失调。鉴于这些事实，该应用的总体目标是阐明分子机制以及将多胺与 BABS 和 SRS 连接起来的代谢途径，并测试多胺靶向剂（DFMO、 Me2Spm 等）在转基因 BABS 和 SRS 小鼠模型以及人类患者来源的原代细胞中淋巴母细胞系。以下具体目标旨在实现这些目标。目标 1：表征并通过药物治疗模拟个体 ODC1 功能获得性突变的基因小鼠模型与 BABS 一起探究控制人类 BABS 患者表型的分子机制。目标 2：优化受 SRS 影响个体的细胞和新型遗传小鼠模型的药物治疗模仿 SRS 患者的常见突变。目标 3：扩大对 BABS 和 SRS 的临床理解改善越来越多的罕见疾病的临床护理。由于该提案的主要目的是定义控制 BABS 和 SRS 的分子机制和代谢途径，并测试为了验证相关模型中治疗的有效性，我们使用特定于疾病的小鼠模型至关重要。我们将使用我们之前发布的 BABS 和 SRS 小鼠模型以及患者来源的细胞系，确定多胺抑制剂治疗的体内有效性。我们的研究提供了难得的机会有可能治愈或至少改善两种人类遗传性疾病 BABS 和 SRS 的症状。