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

点击翻译按钮获取中文摘要

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.