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

项目摘要 长链脂肪酸氧化紊乱(LC-FAOD)是一组异质性疾病，其特征是 无法分解线粒体中的长链脂肪酸以获取能量。受影响的主要组织有 肝脏、心脏和肌肉。这些疾病在出生时就通过新生儿筛查计划进行识别。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。 尽管几十年来给患者口服含有MCFA的油，但人们并不了解MCFA是如何 由肝脏、肌肉和心脏代谢的。此外，关于治疗性药物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 锻炼能力。人类患者同样也会出现肌肉症状和横纹肌溶解。在 目前的建议认为，目前以MCFA为基础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。第二，口服MCFA是 几乎完全被肝脏吸收，并确实分布到心脏和肌肉。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 中链类脂种类和替代给药途径。这一假设得到了初步数据的支持 表明心脏和肌肉更喜欢MCFA(MC-肉碱)的肉碱结合物，而不是游离的MCFA，并且 皮下注射MC-A对LC-FAOD小鼠肌肉功能的改善作用 肉碱。这一假设将在三个具体目标中得到充分探讨：1)确定最优中间链 肝脏、心脏和肌肉的脂质种类；2)确定口服和口服的生物利用度和分布 皮下注射中链脂肪；3)确定中链脂肪的治疗效果 LC-Fod小鼠体内的脂类。目标1有望表明肝脏更喜欢以游离MCFA为底物，而肌肉和 心脏偏爱MC-肉碱。这种不同的偏好被认为是由于线粒体的存在。 中链酰辅酶A合成酶在肝脏中，但不在心脏或肌肉中。预计AIM 2将证明 中链脂类的皮下给药大大提高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有望记录 Aim 1的优化底物和Aim 2的皮下给药的治疗优势 该项目的结果将为更个性化、针对症状的MCFA应用奠定基础。 LC-FOOD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.