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Acetate Supplementation as a therapeutic strategy for Canavan disease

补充乙酸作为卡纳万病的治疗策略

基本信息

批准号：
8803820
负责人：
ARYAN Mangalam NAMBOODIRI
金额：
$ 18.99万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8803820
关键词：
10 year old Acetates Acetyl Coenzyme A Adolescence Affect Animal Model Antiepileptic Agents Aspartoacylase Biochemical Birth Brain Canavan Disease Cessation of life Characteristics Child Chronic Clinical Clinical Trials Development Developmental Delay Disorders Diet Disease Dose Enteral Feeding Enzyme Gene Etiology Family Food Galactosylceramides Gene Expression Regulation Genes Glycogen Phosphorylase Goals Health Hearing Histone Acetylation Inborn Errors of Metabolism Infant Knockout Mice Lipids Metabolic Pathway Methods Modeling Motor Muscle Weakness Mutation Myelin N-acetylaspartate Neurodegenerative Disorders Neurons Oligodendroglia Outcome Paralysed Patients Performance Phenotype Rattus Replacement Therapy Safety Schedule Seizures Source Staging Supplementation Testing Therapeutic Time Tremor Vision Water Weaning critical period dysmyelination effective therapy efficacy testing feeding galactocerebroside gene therapy improved in vivo Model mouse model myelination nervous system disorder postnatal preclinical study pyruvate dehydrogenase response stem cell therapy success

项目摘要

DESCRIPTION (provided by applicant): Canavan disease (CD) is a rare neurological disease resulting from genetic defects that manifest as a progressive neurodegenerative disease leading to paralysis and death, usually between 3 and 10 years of age. There is no effective treatment at the present time. CD is caused by mutations in the gene for the enzyme aspartoacylase (ASPA), which produces free acetate from the concentrated brain metabolite N-acetylaspartate (NAA). NAA is synthesized in neurons, but ASPA is expressed in oligodendrocytes, and evidence indicates that neurons transfer NAA to oligodendrocytes for acetyl CoA synthesis. Because acetyl CoA is a key building block for myelin lipid synthesis, and other critical developmental functions such as gene regulation through histone acetylation, we postulated that the inability to enzymatically catabolize NAA leads to an acetate deficiency in oligodendrocytes during postnatal CNS myelination, resulting in oligodendrocyte death and defective myelin lipid synthesis. We tested the hypothesis that dietary acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of CD. Glyceryl-triacetate (GTA), a hydrophobic acetate source, was administered to tremor rats starting 7 days after birth, and administration was continued in food and water after weaning. Significant improvements were observed in motor performance. Further, the characteristic brain vacuolation associated with CD was modestly reduced by the treatment. The improvements in motor performance were positively correlated with the decreased vacuolation. Our central hypothesis continues to be that the inability to catabolize NAA leads to a brain acetate (acetyl CoA) deficiency during a critical period of CNS development, impairing myelination and other aspects of brain development. Currently, our acetate supplementation therapy has proved only partially effective in animal models of CD. We plan to test additional acetate/acetyl CoA sources alone and in combination to improve outcomes further. We have already identified five such test compounds. These compounds increase acetyl CoA by different biochemical mechanisms. Therefore, we are likely to achieve additive or synergetic effects in combination studies. Specific Aim 1 is to determine the time course and dose response of the test compounds to increase acetyl CoA in brain and subsequently determine efficacy of the test compounds and their combinations in our in vivo model of CD using optimal dose and dosing schedules. Specific Aim 2 is to determine the long term safety of the treatment with chronic administration in order to proceed as quickly as possible to prepare the method for clinical trials. Importance of the proposed studies lies in the fact that CD has no current treatment and remains a fatal disease which is devastating to the affected families. Acetate replacement therapy is a simple biochemical approach, which is safe, inexpensive and convenient for use in CD infants. Preclinical studies have shown that GTA is safe to use in infants, but the treatment still requires further improvements and optimization.

描述（由申请人提供）：卡纳万病 (CD) 是一种由遗传缺陷引起的罕见神经系统疾病，表现为进行性神经退行性疾病，导致瘫痪和死亡，通常在 3 至 10 岁之间。目前尚无有效的治疗方法。 CD 是由天冬氨酸酰基酶 (ASPA) 基因突变引起的，该酶从浓缩的脑代谢物 N-乙酰天冬氨酸 (NAA) 中产生游离乙酸。 NAA 在神经元中合成，但 ASPA 在少突胶质细胞中表达，有证据表明神经元将 NAA 转移到少突胶质细胞中合成乙酰 CoA。由于乙酰辅酶A是髓磷脂脂质合成和其他关键发育功能（例如通过组蛋白乙酰化进行基因调节）的关键组成部分，因此我们推测，无法酶促分解代谢NAA会导致出生后中枢神经系统髓鞘形成过程中少突胶质细胞中乙酸盐的缺乏，从而导致少突胶质细胞死亡和髓鞘脂质合成缺陷。我们使用 CD 震颤大鼠模型检验了以下假设：出生后髓鞘形成过程中膳食醋酸补充剂可改善与 ASPA 缺乏相关的严重表型。三乙酸甘油酯 (GTA) 是一种疏水性醋酸盐来源，从出生后 7 天开始给予震颤大鼠，并在断奶后继续在食物和水中给药。观察到运动性能显着改善。此外，与 CD 相关的特征性脑空泡化通过治疗适度减少。运动性能的改善与空泡形成的减少呈正相关。我们的中心假设仍然是，在中枢神经系统发育的关键时期，无法分解代谢 NAA 会导致大脑醋酸盐（乙酰辅酶 A）缺乏，从而损害髓鞘形成和大脑发育的其他方面。目前，我们的醋酸盐补充疗法已被证明在克罗恩病动物模型中仅部分有效。我们计划单独或组合测试额外的乙酸/乙酰 CoA 来源，以进一步改善结果。我们已经确定了五种这样的测试化合物。这些化合物通过不同的生化机制增加乙酰辅酶A。因此，我们很可能在联合研究中实现相加或协同效应。具体目标1是确定测试化合物增加脑中乙酰辅酶A的时间过程和剂量反应，并随后使用最佳剂量和给药方案确定测试化合物及其组合在我们的CD体内模型中的功效。具体目标2是确定长期给药治疗的长期安全性，以便尽快为临床试验方法做好准备。拟议研究的重要性在于，CD 目前尚无治疗方法，并且仍然是一种致命疾病，对受影响的家庭来说是毁灭性的。醋酸盐替代疗法是一种简单的生化方法，安全、廉价且方便，适用于 CD 婴儿。临床前研究表明，GTA在婴儿中使用是安全的，但治疗仍需进一步改进和优化。