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）：白细胞营养不良是一组影响髓磷脂的疾病。大多数白细胞营养不良是遗传性的，并导致白质的逐渐变性。当前，没有任何白细胞营养不良的治疗方法。该项目的重点是最近鉴定出的白细胞营养不良，这是由2-羟化酶（FA2H）基因突变引起的，导致缺乏类型的髓磷脂脂质。由于该疾病是由脂质缺乏引起的，因此可以通过替换丢失的脂质来治疗的可能性很明显。这项研究的最终目的是开发可以纠正患者髓磷脂脂质缺陷的合成脂质疗法，从而防止白质的变性。该项目是一项临床前研究，旨在使用FA2H敲除小鼠模型开发潜在的脂质疗法。 FA2H是一种负责合成主要髓磷脂鞘脂的脂质生物合成酶。含半乳糖的鞘脂（半乳脂）约占总髓脂脂质的30％。超过一半的髓鞘半乳脂包含2-羟基脂肪酸（HFA）作为N-酰基链（HFA-Galactolipids）。 FA2H是负责髓磷脂形成细胞中前体HFA合成的酶。 FA2H缺乏导致髓磷脂果脂中HFA的损失，最终导致白质变性。如果外源提供足够的HFA，可以预防残疾的白细胞营养不良。为了探索这种可能性，合成HFA脂质将通过饮食对FA2H-敲除小鼠施用。实验旨在解决以下三个问题：1）HFA脂质是否吸收？ 2）外源HFA是否掺入髓鞘半乳脂？ 3）长期给予HFA脂质会引起任何不利影响吗？ 该研究将分为三个阶段。在初始阶段，FA2H+/+和FA2H - / - 断奶将被喂食，并补充含有HFA（HFA-TAG）的各种合成三酰基甘油（HFA-TAG）5天，以确定是否可以吸收测试脂质。将收集血液样本以确定血浆HFA水平。那些被吸收的HFA标签将经过测试，以将HFA送到髓磷脂。在这项研究的这一阶段，FA2H+/+和FA2H - / - 断奶将被喂食，并补充了HFA-TAG的Chow，持续4周。在4周结束时，将分析脑脂质，以确定HFA-Galactolipids的存在。然后，将测试阳性化合物的长期作用。如果成功，这项研究将导致潜在的治疗剂的发展，以预防和治愈由FA2H缺乏引起的白细胞营养不良。 公共卫生相关性：缺乏FA2H的儿童患有毁灭性白细胞营养不良。幸运的是，最近已经确定了疾病的原因：患者缺乏组成髓鞘的脂肪酸。该项目的目的是开发治疗剂，为患者的髓磷脂提供缺失的脂肪酸，以预防和治愈该疾病。