Phase 2 Study of L-Serine in HSN Type 1

描述(由申请人提供)： 本研究的目的是评价L丝氨酸治疗遗传性感觉神经病1型患者的疗效。遗传性感觉和自主神经病变I型(HSAN1)是一种进行性和衰弱的疾病，目前还没有治疗方法。最近发现了两种新的脱氧狮身人面像碱基(DSB)，它们积聚在HSAN1患者和突变的转基因HSAN1小鼠的血浆中。这种疾病是由编码丝氨酸棕榈酰转移酶(SPT)亚单位的SPTLC1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与丝氨酸反应生成鞘氨酸。这两个新发现的DSB，脱氧鞘氨酸氨基和脱氧甲基鞘氨酸氨基分别由棕榈酰辅酶A与丙氨酸和甘氨酸缩合而成，表明HSAN1突变改变了SPT的氨基酸选择性。为了支持这一假设，研究表明，人类和小鼠体内的DSB水平可以通过补充该酶的正常底物丝氨酸来降低。在这项随机、双盲、安慰剂对照的研究中，20名甲型HSAN1病毒研究参与者将被分配到10名受试者中，分别服用L丝氨酸(400 mg/kg/d)和安慰剂，每人治疗24个月。HSAN1的进展将通过建立的临床分级标准和皮肤活检的表皮内神经纤维密度(IENFD)的测量来衡量。失败的百分比[Charcot Marie Tooth神经评分(CMTNS)临床下降1分或IENFD下降30%]将每隔6个月评估一次。如果服用安慰剂的患者失败，他们将被切换到L-丝氨酸。将在12个月和18个月时进行中期分析，以评估有效性和无效性，因此研究将停止或继续。

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.