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

描述（由申请方提供）：研究目的是确定400 mg/kg/天口服L-丝氨酸是否足够安全和耐受，是否具有充分验证的神经保护机制，以证明在未来的遗传性感觉和自主神经病1型（HSAN 1）III期试验中进行进一步研究的合理性。遗传性感觉和自主神经病变I型（HSAN 1）是一种进行性和衰弱性疾病，目前没有治疗方法。我们最近发现了两种新的脱氧鞘脂（dSL），积累在血浆中的HSAN 1患者和突变转基因HSAN 1小鼠。这种疾病是由编码丝氨酸棕榈酰转移酶（SPT）亚基的SPTLC 1基因的错义突变引起的。在正常情况下，SPT酶催化棕榈酰辅酶A与丝氨酸反应形成二氢鞘氨醇。两个新鉴定的dSL，脱氧神经鞘氨醇和脱氧甲基神经鞘氨醇，分别由棕榈酰辅酶A与丙氨酸和甘氨酸的缩合产生，表明HSAN 1突变改变SPT的氨基酸选择性。为了支持这一假设，我们已经表明，人和小鼠中的dSL水平可以通过补充酶的正常底物丝氨酸来降低。在这项随机、双盲、安慰剂对照研究中，我们将入组20例HSAN 1研究受试者，其中10例受试者分配至L-丝氨酸（400 mg/kg/d）组，10例分配至安慰剂组，各治疗1年，然后所有受试者交叉至L-丝氨酸再治疗1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，基线时安慰剂提供dSL水平昼夜模式的信息，第1年时活性组提供稳定背景基础上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指标的影响。我们将研究现有的感觉神经病变，神经生理学措施和表皮内神经纤维密度的神经系统评级量表，并评估其变异性和敏感性L-丝氨酸干预。重要的是，它将让我们决定未来III期试验的最佳结局指标。

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.