Safety, Tolerability and Biological Activity of L-serine in HSAN1.

HSAN1 中 L-丝氨酸的安全性、耐受性和生物活性。

基本信息

批准号：
8720080
负责人：
FLORIAN S EICHLER
金额：
$ 10.26万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720080
关键词：
Affect Affinity Alanine Amino Acids Biochemical Biological Biopsy Clinical Clinical Trials Disease Disease Progression Double-Blind Method Drug Kinetics Enrollment Environment Enzymes Floods Future Genes Genetic Crossing Over Glycine Hereditary Sensory Neuropathy Human Intervention Investigation Lipids Lower Extremity Measures Missense Mutation Modeling Mus Mutant Strains Mice Mutation Nerve Degeneration Nerve Fibers Neurologic Neuropathy Neurotoxins Numbness Oral Outcome Measure Pain Palmitoyl Coenzyme A Participant Patients Pattern Phase III Clinical Trials Phenotype Physical condensation Pilot Projects Placebos Plasma Randomized Reaction Reducing diet Relative (related person)Reporting Research Safety Sensory Series Serine Skin Sphingolipids Supplementation Therapeutic Intervention Transgenic Organisms arm autonomic neuropathy density gene discovery improved mutant neuropathology neurophysiology neurotoxic novel placebo controlled study public health relevance research study sensory neuropathy serine palmitoyltransferase sphinganine

项目摘要

DESCRIPTION (provided by applicant): The study objective is to determine whether 400 mg/kg/day oral L-serine is sufficiently safe and tolerable and possesses an adequately verified neuroprotective mechanism to justify further investigation in a future phase III trial in hereditar sensory and autonomic neuropathy type 1 (HSAN1). Hereditary sensory and autonomic neuropathy type I (HSAN1) is a progressive and debilitating illness for which currently no treatment exists. We recently identified two novel deoxysphingolipids (dSL) that accumulate in plasma of HSAN1 patients and mutant transgenic HSAN1 mice. The disease is caused by missense mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase (SPT). In normal circumstances the SPT enzyme catalyzes the reaction of palmitoyl-CoA with serine to form sphinganine. The two newly identified dSL, deoxysphinganine and deoxymethylsphinganine, arise from condensation of palmitoyl-CoA with alanine and glycine respectively, suggesting that HSAN1 mutations alter amino acid selectivity of SPT. In support of this hypothesis we have shown that levels of dSL in humans and mice can be lowered by supplementation with the enzyme's normal substrate, serine. In this randomized, double-blind, placebo-controlled study we will enroll 20 research participants with HSAN1 with 10 subjects assigned to L-serine (400mg/kg/d) and 10 assigned to placebo who are each treated for 1 year, followed by cross-over to L-serine by all participants for one additional year. Pharmacokinetic studies will occur at the start of the first and second year allowing us to complete two PK series, with placebo at baseline providing information on diurnal patterns of dSL levels and an active arm at 1 year providing information on PK of L-serine on top of a stable background. Further, we will determine the impact of long-term reduction of dSL levels relative to neuropathy measures. We will study an existing neurological rating scale of sensory neuropathy, neurophysiological measures and intraepidermal nerve fiber density and assess their variability and sensitivity to L-serine intervention. Importantly it will let us decide on th best outcome measure for future Phase III trials.

描述（由申请人提供）：研究目的是确定400 mg/kg/kg/day口服L-丝氨酸是否足够安全可容纳，并具有经过验证的神经保护机制，以在遗传性神经疾病和自治性神经疾病1型1（HSAN1）中在未来的III期试验中证明进一步的研究（HSAN1）。遗传性感觉和自主神经病I型（HSAN1）是一种进步且令人衰弱的疾病，目前尚无治疗。我们最近确定了两种新型的脱氧脂脂（DSL），它们积累在HSAN1患者和突变的转基因HSAN1小鼠的血浆中。该疾病是由SPTLC1基因中的错义突变引起的，该基因编码酶丝氨酸棕榈酰转移酶（SPT）的亚基。在正常情况下，SPT酶会催化棕榈酰辅酶A与丝氨酸的反应形成鞘氨酸。这两个新鉴定的DSL分别是由棕榈酰-COA与丙氨酸和甘氨酸的凝结产生的，这表明HSAN1突变改变了SPT的氨基酸选择性。为了支持这一假设，我们已经表明，可以通过补充酶的正常底物丝氨酸来降低人类和小鼠的DSL水平。在这项随机，双盲，安慰剂对照的研究中，我们将招募20名HSAN1的研究参与者，其中10名受试者分配给L-塞林（400mg/kg/d），将10个受试者分配给安慰剂，每人都接受了1年的治疗，然后将所有参与者交叉到L-Serine conter-over cotherine一年。药代动力学研究将在第一年和第二年开始时进行，使我们能够完成两个PK系列，其安慰剂在基线上提供有关DSL水平的昼夜模式的信息，并在1年的1年内提供一个主动臂，从而在稳定背景的顶部提供了有关L serine的信息。此外，我们将确定相对于神经病措施的长期降低DSL水平的影响。我们将研究感觉神经病，神经生理学措施和epi骨内神经纤维密度的现有神经学评级量表，并评估其对L塞罗干预的可变性和敏感性。重要的是，它将让我们决定未来III期试验的最佳结果度量。