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: 10570196
• 负责人: ERIC S GOETZMAN
• 金额: $ 33.9万
• 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/10570196
• 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; Consumption; Data; Defect; Devices; Diet; Disease; Dose; Drug Delivery Systems; 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; Neonatal Screening; Oils; Oral; Oral Administration; Patients; Preclinical Testing; Refractory; Research; Rhabdomyolysis; Route; Self Administration; Subcutaneous Injections; Symptoms; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; absorption; acylcarnitine; efficacy evaluation; exercise capacity; fatty acid oxidation; improved; ketogenesis; long chain fatty acid; mouse model; preclinical efficacy; preference; screening program; subcutaneous; usability

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-FAODS）是一组异性疾病，其特征是 无法分解线粒体中的长链脂肪酸的能量。受影响的主要组织是 肝，心脏和肌肉。这些疾病是通过新生儿筛查计划在出生时确定的。治疗 包括避免禁食和用中链脂肪酸（MCFA）代替饮食中的长链脂肪。 尽管有数十年的口服含MCFA油的口服剂量患者，但尚不了解MCFA是如何的 由肝脏，肌肉和心脏代谢。此外，关于治疗的实验证据的严格性 口服MCFA的功效很低。在LC-FAOD的小鼠模型中，口服MCFA不能改善​​心肌病或 运动能力。人类患者同样仍然患有肌肉症状和横纹肌溶解。在 当前的提议假定目前基于MCFA的疗法有两个主要问题。第一的， 肌肉和心脏不具备代谢外源MCFA。第二，口头管理的MCFA是 几乎完全被肝脏吸收，并确实分散到心脏和肌肉。假设MCFA 可以通过探索替代方案来优化治疗以治疗心肌病和横纹肌溶解 中链脂质物种和替代性递送途径。该假设由初步数据支持 表明心脏和肌肉更喜欢MCFA（MC-Carnitines）的肉碱缀合物，而不是自由MCFA，一个 在皮下注射MC-的情况下，LC-FAOD小鼠的肌肉功能改善了 肉碱。该假设将在三个特定目的中充分探讨：1）确定最佳中链 肝脏，心脏和肌肉的脂质物种； 2）确定口服的生物利用度和生物分布 皮下注射的中链脂质； 3）确定中链的治疗功效 LC-FAOD小鼠中的脂质。 AIM 1预计将表明肝脏更喜欢自由MCFA作为底物，而肌肉和肌肉和 心脏更喜欢MC肉碱。提出差异偏好是由于存在线粒体的存在 肝脏中的中链酰基-COA合酶，而不是心脏或肌肉。 AIM 2有望证明 中链脂质的皮下递送大大增加了生物利用度，随后的生物分布 外围。最后，在AIM 3中，LC-FAOD鼠标模型的临床前测试有望记录 AIM 1的优化底物和AIM 2的皮下传递的治疗优势。 该项目的结果将为MCFA-的更个性化的特定于症状的应用奠定基础。 LC-FAOD患者的基于疗法。