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。

• 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
• 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

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/天口服 L-丝氨酸是否足够安全和​​可耐受，并具有经过充分验证的神经保护机制，以证明未来 1 型遗传性感觉和自主神经病 (HSAN1) III 期试验中进一步研究的合理性。 I 型遗传性感觉和自主神经病 (HSAN1) 是一种进行性、使人衰弱的疾病，目前尚无治疗方法。我们最近发现了两种新型脱氧鞘脂 (dSL)，它们在 HSAN1 患者和突变型转基因 HSAN1 小鼠的血浆中积累。该疾病是由编码丝氨酸棕榈酰转移酶 (SPT) 亚基的 SPTLC1 基因错义突变引起的。正常情况下，SPT酶催化棕榈酰辅酶A与丝氨酸反应形成二氢鞘氨醇。新发现的两种 dSL，脱氧二氢鞘氨醇和脱氧甲基二氢鞘氨醇，分别由棕榈酰辅酶 A 与丙氨酸和甘氨酸缩合产生，表明 HSAN1 突变改变了 SPT 的氨基酸选择性。为了支持这一假设，我们已经证明，通过补充酶的正常底物丝氨酸可以降低人和小鼠的 dSL 水平。在这项随机、双盲、安慰剂对照研究中，我们将招募 20 名 HSAN1 研究参与者，其中 10 名受试者分配至 L-丝氨酸（400mg/kg/d），10 名受试者分配至安慰剂，每人接受治疗 1 年，然后所有参与者交叉至 L-丝氨酸再治疗一年。 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，基线安慰剂提供 dSL 水平的昼夜模式信息，第 1 年活性组提供稳定背景下 L-丝氨酸 PK 的信息。此外，我们将确定 dSL 水平长期降低相对于神经病变措施的影响。我们将研究现有的感觉神经病神经学评定量表、神经生理学测量和表皮内神经纤维密度，并评估它们的变异性和对 L-丝氨酸干预的敏感性。重要的是，它将让我们决定未来 III 期试验的最佳结果衡量标准。