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

项目摘要 长链脂肪酸氧化障碍（LC-FAODs）是一组异质性障碍，其特征在于： 无法分解线粒体中的长链脂肪酸以获得能量。受影响的主要组织是 肝脏心脏和肌肉这些疾病在出生时通过新生儿筛查计划确定。治疗 包括禁食避免和用中链脂肪酸（MCFA）取代饮食中的长链脂肪。 尽管数十年来患者口服含MCFA的油，但尚不清楚MCFA是如何影响患者的健康的。 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的功效较低。在LC-FAOD的小鼠模型中，口服MCFA不能改善心肌病或 锻炼的能力。人类患者同样仍然遭受肌肉症状和横纹肌溶解。在 根据目前的提议，假设目前基于MCFA的疗法存在两个主要问题。第一、 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。假设MCFA 通过探索替代疗法， 中链脂质种类和替代递送途径。这一假设得到了初步数据的支持 显示心脏和肌肉比游离MCFA更喜欢MCFA的肉毒碱缀合物（MC-肉毒碱），并且 证明皮下注射MC-后LC-FAOD小鼠的肌肉功能得到改善 肉毒碱这一假设将在三个具体目标中得到充分探讨：1）确定最佳的中间链 肝脏、心脏和肌肉的脂质种类; 2）确定口服与口服的生物利用度和生物分布。 皮下施用中链脂质;和3）确定中链脂质的治疗功效。 LC-FAOD小鼠中的脂质。目的1预期显示肝脏偏好游离MCFA作为底物，而肌肉和 心脏更喜欢MC-肉碱。不同的偏好被认为是由于线粒体的存在， 肝脏中的中链酰基辅酶A脱氢酶，而不是心脏或肌肉。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，预期LC-FAOD小鼠模型的临床前测试将记录 目的1的优化底物和目的2的皮下递送的治疗优势。的 该项目的结果将为MCFA的更个性化、更具体的应用奠定基础- LC-FAOD患者的基础治疗。

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.