Acetate Supplementation as a therapeutic strategy for Canavan disease

补充乙酸作为卡纳万病的治疗策略

• 批准号: 8700038
• 负责人: ARYAN Mangalam NAMBOODIRI
• 金额: $ 22.79万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700038
• 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; Enzyme Gene; Etiology; Family; Food; Galactosylceramides; Gene Expression Regulation; Genes; Glycogen Phosphorylase; Goals; 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; public health relevance; pyruvate dehydrogenase; response; stem cell therapy; success; tube feeding

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）是一种罕见的神经系统疾病，由遗传缺陷引起，表现为进行性神经退行性疾病，通常在3至10岁之间导致瘫痪和死亡。目前没有有效的治疗方法。CD是由β-乙酰基酰化酶（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，并且证据表明神经元将NAA转移到少突胶质细胞用于乙酰辅酶A合成。由于乙酰辅酶A是髓鞘脂质合成的关键组成部分，以及其他重要的发育功能，如通过组蛋白乙酰化的基因调控，我们假设，不能酶促分解代谢NAA导致乙酸缺乏症少突胶质细胞在出生后CNS髓鞘形成，导致少突胶质细胞死亡和髓鞘脂质合成缺陷。我们使用震颤大鼠CD模型测试了以下假设：出生后髓鞘形成期间膳食乙酸补充剂将改善与ASPA缺乏相关的严重表型。三乙酸甘油酯（GTA）是一种疏水性乙酸酯来源，出生后7天开始给予震颤大鼠，断奶后继续在食物和水中给药。在运动性能方面观察到显著改善。此外，与CD相关的特征性脑空泡化通过治疗适度减少。运动表现的改善与空泡化的减少呈正相关。我们的中心假设仍然是，在中枢神经系统发育的关键时期，不能分解代谢NAA导致脑乙酸（乙酰辅酶A）缺乏，损害髓鞘形成和脑发育的其他方面。目前，我们的醋酸盐补充疗法已被证明在CD动物模型中仅部分有效。我们计划单独测试额外的乙酸/乙酰辅酶A来源，并结合使用，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，我们可能在联合研究中实现累加或协同效应。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，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，以便尽快进行临床试验方法的准备。拟议研究的重要性在于，CD目前没有治疗方法，仍然是一种致命的疾病，对受影响的家庭具有毁灭性的影响。醋酸盐替代疗法是一种简单的生化方法，安全、廉价、方便地用于CD婴儿。临床前研究表明，GTA在婴儿中使用是安全的，但治疗仍需要进一步改进和优化。