Dose Optimization of Nervonic Acid - a Potential Therapy to Alleviate Disease Progression in Adrenoleukodystrophy

摘要 肾上腺脑白质营养不良（ALD）是一种罕见的X连锁疾病，由缺陷的转运蛋白引起， 过氧化物酶体脂肪酸氧化所需的。这会导致长链脂肪酸的积累 （VLCFA），一个重要的和证明的贡献者与ALD相关的神经损伤。这种疾病是 与几种神经学表型相关，基因型或生化特征都不能 预测它的轨迹最具破坏性的结果是脑ALD患者，约50% 男孩在出现临床症状后5年内死于该病。添加ALD 在全国新生儿筛查小组中， 有ALD突变如果不治疗，所有携带这种突变的人，包括女性携带者， 最终会出现渐进的神经系统症状 目前还没有批准的治疗方法可用于症状前患者，可以降低VLCFA水平， 以便延迟或阻止疾病进展。先前已经表明，膳食单不饱和脂肪酸 酸如芥酸可减少VLCFA积累。直到最近，一种研究药物，洛伦佐的 家庭可获得由芥酸和油酸混合而成的油。然而，其发展 由于缺乏商业赞助商，最近停止了，因此该产品在美国无法使用 States.因此，迫切需要安全有效的治疗，可以向这些患者提供治疗， 改变病程。在这里，我们建议进行一个精心设计的药理学研究神经酸， 单不饱和脂肪酸，以确定最佳剂量，是安全的长期使用，并可以有代谢 在ALD临床前模型中的益处。 我们假设，临床相关浓度的神经酸将具有类似于 芥子酸。为了评估神经酸的临床前治疗潜力，我们建议进行 精心设计的安慰剂对照实验在目标1中，我们将评估神经酸在 ALD小鼠模型。通过结合剂量范围和药代动力学研究，我们预计 确定神经酸的暴露（浓度）-反应（VLCFA降低）关系，和 确认其安全性。在目标2中，我们将评估神经酸的长期影响，并验证暴露- 反应关系。我们期望利用经过验证的确认-响应关系（PK-PD模型） 确定理想的神经酸剂量，用于未来ALD患者的临床试验。 影响：尽管观察到洛伦佐油在ALD中的益处，但缺乏关于其药理学的信息， 包括确定-响应关系，限制了其临床应用。在这个临床试验准备 通过研究，我们将对神经酸有一个清晰的药理学认识，这将有助于翻译 用于人类使用，并增加成人和ALD症状前男孩研究成功的可能性。

Abstract Adrenoleukodystrophy (ALD) is a rare X-linked disorder caused by a defective transporter protein, which is required for peroxisomal fatty acid oxidation. This results in accumulation of very long-chain fatty acids (VLCFA), an important and proven contributor to the nerve injury associated with ALD. This disease is associated with several neurological phenotypes and neither genotype nor biochemical characteristics can predict its trajectory. The most devastating outcome is for patients with cerebral ALD, with approximately 50% boys succumbing to their disease within 5 years after the onset of clinical symptoms. With the addition of ALD in the newborn screening panel across the country, there is an increase in the number of patients identified with an ALD mutation. If left untreated, all individuals with this mutation, including female carriers, will eventually develop progressive neurological symptoms. Currently there is no approved treatment available to pre-symptomatic patients that can lower VLCFA levels, so as to delay or arrest disease progression. It has been shown previously that dietary monounsaturated fatty acids such as erucic acid can decrease VLCFA accumulation. Until recently an investigational drug, Lorenzo’s oil, which is a mixture of erucic and oleic acids, was available for families. However, its development has stopped recently due to the lack of commercial sponsors and thus this product is unavailable in the United States. Thus, there is a critical need for safe and effective treatments, which can be offered to these patients to alter disease course. Here we propose to conduct a well-designed pharmacological study of nervonic acid, a monounsaturated fatty acid, to determine optimal doses that is safe for prolonged use and can have metabolic benefits in an ALD preclinical model. We hypothesize that clinically-relevant concentrations of nervonic acid will have therapeutic efficacy similar to erucic acid. In order to assess the preclinical therapeutic potential of nervonic acid, we propose to conduct well-designed, placebo-controlled experiments. In Aim 1, we will assess the effects of nervonic acid in an ALD mouse model. Using a combination of dose-ranging and pharmacokinetic studies, we expect to determine the exposure (concentrations)-response (decrease in VLCFA) relationship of nervonic acid, and confirm its safety. In Aim 2 we will evaluate the long-term effects of nervonic acid and validate exposure- response relationships. We expect to utilize the validated exposure-response relationships (PK-PD models) to identify ideal nervonic acid dosages for future clinical trials in patients with ALD. Impact: Despite the observed benefits of Lorenzo’s oil in ALD, the lack of information on its pharmacology, including exposure-response relationships, has limited its clinical application. In this clinical trial readiness study, we will develop a clear pharmacological understanding of nervonic acid, which will facilitate translation to human use and increase the likelihood of success for studies in adults and pre-symptomatic boys with ALD.