Optimizing medium-chain lipids for the treatment of long-chain fatty acid oxidation disorders

优化中链脂质用于治疗长链脂肪酸氧化紊乱

• 批准号: 10372915
• 负责人: ERIC S GOETZMAN
• 金额: $ 33.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372915
• 关键词: Acyl Coenzyme A; Affect; Biodistribution; Bioenergetics; Biological Availability; Biology; Birth; Bypass; C10; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carnitine; Carnitine O-Acetyltransferase; Cells; Coenzyme A; Consumption; Data; Defect; Devices; Diet; Disease; Dose; Drug Delivery Systems; Energy Therapy; Enzymes; Fasting; Fatty acid glycerol esters; Future; Heart; Heart Mitochondria; Hepatocyte; Human; Individual; Ketones; Lipids; Liver; Liver Mitochondria; Measures; Medium chain fatty acid; Mitochondria; Mitochondrial Matrix; Mus; Muscle; Muscle Mitochondria; Muscle function; Myocardium; Neonatal Screening; Oils; Oral; Oral Administration; Oxides; Patients; Preclinical Testing; Refractory; Research; Rhabdomyolysis; Route; Self Administration; Subcutaneous Injections; Symptoms; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; acylcarnitine; base; efficacy evaluation; exercise capacity; fatty acid oxidation; improved; ketogenesis; long chain fatty acid; mouse model; preclinical efficacy; preference; screening program; subcutaneous

Project Abstract Long-chain fatty acid oxidation disorders (LC-FAODs) are a heterogenous group of disorders characterized by the inability to break down long-chain fatty acids in the mitochondria for energy. The primary tissues affected are liver, heart, and muscle. These disorders are identified at birth through newborn screening programs. Treatment consists of fasting avoidance and replacing long-chain fats in the diet with medium-chain fatty acids (MCFA). Despite decades of orally dosing patients with MCFA-containing oils, it is not understood how MCFA are metabolized by liver, muscle, and heart. Further, the rigor of the experimental evidence regarding the therapeutic efficacy of oral MCFA is low. In mouse models of LC-FAOD, oral MCFA do not improve cardiomyopathy or the capacity for exercise. Human patients likewise still suffer from muscle symptoms and rhabdomyolysis. In the current proposal it is postulated that there are two major problems with current MCFA-based therapies. First, muscle and heart are not equipped to metabolize exogenous MCFA. Second, orally-administered MCFA are nearly completely absorbed by the liver and do distribute to heart and muscle. It is hypothesized that MCFA therapy can be optimized to treat cardiomyopathy and rhabdomyolysis through the exploration of alternative medium-chain lipid species and alternative routes of delivery. The hypothesis is supported by preliminary data showing that heart and muscle prefer carnitine conjugates of MCFA (MC-carnitines) over free MCFAs, and a demonstrated improvement in muscle function of LC-FAOD mice upon subcutaneous injection of an MC- carnitine. This hypothesis will be fully explored in three Specific Aims: 1) Determine the optimal medium-chain lipid species for liver, heart and muscle; 2) Determine the bioavailability and biodistribution of orally versus subcutaneously-administered medium-chain lipids; and 3) Determine the therapeutic efficacy of medium-chain lipids in LC-FAOD mice. Aim 1 is expected to show that liver prefers free MCFA as substrates, while muscle and heart prefer MC-carnitines. The differential preference is proposed to be due to the presence of mitochondrial medium-chain acyl-CoA synthases in liver but not heart or muscle. Aim 2 is expected to demonstrate that subcutaneous delivery of medium-chain lipids greatly increases bioavailability and subsequent biodistribution to the periphery. Finally, in Aim 3, pre-clinical testing of LC-FAOD mouse models is expected to document the therapeutic advantage of the optimized substrates from Aim 1 and the subcutaneous delivery from Aim 2. The results of this project will lay the groundwork for more personalized, symptom-specific application of MCFA- based therapies in LC-FAOD patients.

项目摘要 长链脂肪酸氧化障碍 (LC-FAOD) 是一组异质性疾病，其特征为 无法分解线粒体中的长链脂肪酸来获取能量。受影响的主要组织是 肝脏、心脏和肌肉。这些疾病是通过新生儿筛查项目在出生时发现的。治疗 包括避免禁食和用中链脂肪酸（MCFA）替代饮食中的长链脂肪。 尽管数十年来患者一直口服含 MCFA 的油，但人们仍不清楚 MCFA 的作用原理。 由肝脏、肌肉和心脏代谢。此外，有关治疗的实验证据的严谨性 口服 MCFA 的疗效较低。在 LC-FAOD 小鼠模型中，口服 MCFA 不能改善心肌病或心肌病 运动能力。人类患者同样仍然患有肌肉症状和横纹肌溶解症。在 目前的提案假设当前基于 MCFA 的疗法存在两个主要问题。第一的， 肌肉和心脏不具备代谢外源 MCFA 的能力。其次，口服MCFA 几乎完全被肝脏吸收并分布到心脏和肌肉。据推测，MCFA 通过探索替代疗法，可以优化治疗心肌病和横纹肌溶解症的方法 中链脂质种类和替代递送途径。该假设得到初步数据的支持 显示心脏和肌肉更喜欢 MCFA 的肉碱结合物（MC-肉碱）而不是游离的 MCFA，并且 皮下注射 MC- 后，LC-FAOD 小鼠的肌肉功能得到改善 肉碱。该假设将在三个具体目标中得到充分探讨：1）确定最佳中链 肝脏、心脏和肌肉的脂质种类； 2) 确定口服与口服药物的生物利用度和生物分布 皮下注射中链脂质； 3) 确定中链的治疗效果 LC-FAOD 小鼠的脂质。目标 1 预计将表明肝脏更喜欢游离 MCFA 作为底物，而肌肉和 心脏更喜欢中链肉碱。差异偏好被认为是由于线粒体的存在 肝脏中存在中链酰基辅酶A合酶，但心脏或肌肉中没有。目标 2 预计将证明 中链脂质的皮下递送大大增加了生物利用度和随后的生物分布 外围。最后，在目标 3 中，LC-FAOD 小鼠模型的临床前测试预计将记录 目标 1 的优化底物和目标 2 的皮下递送的治疗优势。 该项目的结果将为 MCFA 的更加个性化、针对具体症状的应用奠定基础。 LC-FAOD 患者的基础疗法。