Development of lipid therapeutics for fatty acid 2-hydroxylase deficiency

脂肪酸2-羟化酶缺乏症脂质疗法的开发

• 批准号: 7941716
• 负责人: HIROKO HAMA
• 金额: $ 18.44万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941716
• 关键词: Academic Medical Centers; Address; Adverse effects; Affect; Anabolism; Biological Assay; Birth; Blood specimen; Brain; Cells; Ceramides; Child; Childhood; Clinical; Coenzyme A; Collaborations; Complement; Development; Diagnostic tests; Diet; Dihydrosphingosine; Disease; Dystonia; Enzymes; Etiology; Exons; Fatty Acids; Fibroblasts; Figs - dietary; Galactolipids; Galactose; Galactosylceramides; Galactosyltransferases; Genes; Goals; Hereditary Spastic Paraplegia; Human; Hydroxylation; Impaired cognition; Individual; Inherited; Israel; Knockout Mice; Lead; Life; Lipids; Long-Term Effects; Lower Extremity; Maps; Mass Fragmentography; Messenger RNA; Milk; Mixed Function Oxygenases; Mus; Mutation; Myelin; Myelin Sheath; N acylation; N-terminal; Online Mendelian Inheritance In Man; Oral Administration; Pathogenicity; Pathway interactions; Patients; Phase; Plasma; Point Mutation; Proteins; Role; Spastic Paraplegia; Sphingolipids; Sulfoglycosphingolipids; Testing; Therapeutic; Therapeutic Uses; Tissues; Triglycerides; Uridine Diphosphate Galactose; base; design; feeding; human disease; hydroxy fatty acid; leukodystrophy; mouse model; preclinical study; prevent; public health relevance; research study; white matter

DESCRIPTION (provided by applicant): The leukodystrophies are a group of disorders that affect myelin. Most of the leukodystrophies are hereditary and cause progressive degeneration of the white matter. Currently, there are no cures for any of the leukodystrophies. The focus of this project is a recently identified leukodystrophy caused by mutations in the fatty acid 2-hydroxylase (FA2H) gene, which result in lack of a type of myelin lipids. Because this disease is caused by a lipid deficiency, there is a distinct possibility that it could be treatable by replacing the missing lipids. The ultimate goal of this study is to develop synthetic lipid therapeutics that can rectify the deficit in patients' myelin lipids, thereby preventing degeneration of the white matter. This project is a preclinical study aimed at developing potential lipid therapeutics using a Fa2h knockout mouse model. FA2H is a lipid biosynthetic enzyme responsible for the synthesis of major myelin sphingolipids. Galactose-containing sphingolipids (galactolipids) make up approximately 30% of total myelin lipids. More than half of the myelin galactolipids contain 2-hydroxy fatty acids (hFA) as their N-acyl chains (hFA-galactolipids). FA2H is the enzyme responsible for the synthesis of the precursor hFA in myelin-forming cells. FA2H deficiency results in loss of hFA in myelin galactolipids, which eventually leads to degeneration of the white matter. There is a possibility that the disabling leukodystrophy could be prevented if myelin-forming cells are exogenously provided with sufficient hFA. To explore this possibility, synthetic hFA-lipids will be administered to Fa2h- knockout mice through the diet. The experiments are designed to address the following three questions: 1) Are the hFA-lipids absorbed? 2) Are the exogenous hFA incorporated into myelin galactolipids? 3) Does long-term administration of the hFA-lipids cause any adverse effects? The study will be conducted in three phases. In the initial phase, Fa2h+/+ and Fa2h-/- weanlings will be fed milled chow supplemented with various synthetic triacylglycerols containing hFA (hFA-TAG) for 5 days to determine whether the test lipid can be absorbed. Blood samples will be collected to determine plasma hFA levels. Those hFA-TAG that are absorbed will be tested for delivery of hFA to myelin. In this phase of the study, Fa2h+/+ and Fa2h-/- weanlings will be fed milled chow supplemented with the hFA-TAG for 4 weeks. At the end of the 4-week period, brain lipids will be analyzed to determine the presence of hFA-galactolipids. Positive compounds will then be tested for long-term effects. If successful, this study will lead to development of potential therapeutics that will prevent and cure the leukodystrophy caused by FA2H deficiency. PUBLIC HEALTH RELEVANCE: Children with FA2H deficiency suffer from a devastating leukodystrophy. Fortunately, the cause of disease has recently been identified: the patients lack a type of fatty acids that make up myelin sheath. The goal of this project is to develop therapeutics to provide the missing fatty acids to patients' myelin to prevent and cure the disease.

描述（由申请人提供）：脑白质营养不良是一组影响髓鞘的疾病。大多数脑白质营养不良是遗传性的，并引起白色物质的进行性变性。目前，还没有治愈任何脑白质营养不良。该项目的重点是最近发现的由脂肪酸2-羟化酶（FA 2 H）基因突变引起的脑白质营养不良，这导致缺乏一种髓鞘脂质。由于这种疾病是由脂质缺乏引起的，因此有一种明显的可能性，即可以通过补充缺失的脂质来治疗。这项研究的最终目标是开发合成脂质疗法，可以纠正患者髓鞘脂质的缺陷，从而防止白色物质的退化。该项目是一项临床前研究，旨在使用Fa 2 h敲除小鼠模型开发潜在的脂质治疗剂。 FA 2 H是负责主要髓鞘鞘脂合成的脂质生物合成酶。含半乳糖的鞘脂（半乳糖脂）约占总髓鞘脂质的30%。超过一半的髓鞘半乳糖脂含有2-羟基脂肪酸（hFA）作为其N-酰基链（hFA-半乳糖脂）。FA 2 H是负责在髓鞘形成细胞中合成前体hFA的酶。FA 2 H缺乏导致髓鞘半乳糖脂中hFA的损失，这最终导致白色物质的变性。如果髓鞘形成细胞外源性地提供足够的hFA，则有可能预防致残性脑白质营养不良。为了探索这种可能性，将通过饮食向Fa 2 h敲除小鼠施用合成的hFA-脂质。设计实验以解决以下三个问题：1）hFA-脂质被吸收了吗？2)外源性hFA是否掺入髓鞘半乳糖脂中？3)长期给予hFA-脂质是否会引起任何不良反应？ 研究将分三个阶段进行。在初始阶段，将向Fa 2 h +/+和Fa 2 h-/-断奶仔猪饲喂补充有各种含hFA的合成三酰甘油（hFA-TAG）的研磨食物5天，以确定测试脂质是否可以被吸收。将采集血样以测定血浆hFA水平。将测试那些被吸收的hFA-TAG是否将hFA递送至髓磷脂。在该研究阶段，将对Fa 2 h +/+和Fa 2 h-/-断奶仔猪饲喂补充有hFA-TAG的研磨饲料4周。在4周结束时，将分析脑脂质以确定hFA-半乳糖脂的存在。然后将测试阳性化合物的长期影响。如果成功，这项研究将导致潜在的治疗方法的发展，将预防和治愈由FA 2 H缺乏引起的脑白质营养不良。 公共卫生相关性：患有FA 2 H缺乏症的儿童患有毁灭性的脑白质营养不良。幸运的是，最近已经确定了疾病的原因：患者缺乏一种构成髓鞘的脂肪酸。该项目的目标是开发治疗方法，为患者的髓鞘提供缺失的脂肪酸，以预防和治疗疾病。