Phase 2 Study of L-Serine in HSN Type 1

描述（由申请人提供）： 研究目的是评价L-丝氨酸在1型遗传性感觉神经病（HSAN 1）受试者中的疗效。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。最近发现两种新的脱氧鞘氨醇碱（DSB）在HSAN 1患者和突变转基因HSAN 1小鼠的血浆中积累。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DSB，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，它表明，在人类和小鼠中的DSB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，将入组20名患有HSAN 1的研究受试者，其中10名受试者分配至L-丝氨酸（400 mg/kg/d）组，10名分配至安慰剂组，各治疗24个月。HSAN 1的进展将通过已建立的临床评定量表的变化和皮肤活检的表皮内神经纤维密度（IENFD）测量来测量。将以6个月的间隔评估失败百分比[Charcot玛丽牙神经评分（CMTNS）临床下降> 1分或IENFD下降> 30%]。如果安慰剂组的患者治疗失败，将改用L-丝氨酸治疗。将在12个月和18个月时进行中期分析，以评估疗效和无效性，因此将停止或继续研究。

DESCRIPTION (provided by applicant): The study objective is to evaluate the efficacy of L-serine in subjects with hereditary sensory neuropathy type 1 (HSAN1). Hereditary sensory and autonomic neuropathy type I (HSAN1) is a progressive and debilitating illness for which currently no treatment exists. Two novel deoxysphingoid bases (DSB) were recently identified 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 DSB, 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 it is shown that levels of DSB in humans and mice can be lowered by supplementation with the enzyme's normal substrate, serine. In this randomized, double-blind, placebo-controlled study, 20 research participants with HSAN1 will be enrolled with 10 subjects assigned to L-serine (400mg/kg/d) and 10 assigned to placebo who are each treated for 24 months. The progression of HSAN1 will be measured by the change in an established clinical rating scale and measures of intraepidermal nerve fiber density (IENFD) on skin biopsy. The percentage of failures [clinical decline of > 1 point on Charcot Marie Tooth Neurological Score (CMTNS) or > 30% decrease in IENFD] will be assessed at 6 month intervals. If patients in the placebo arm fail, they will be switched to L-serine. There will be an interim analysis at 12 and 18 months to assess for efficacy and futility, and accordingly the study will be stopped or continued.