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

描述(申请人提供)：该研究的目标是确定每天口服L丝氨酸400 mg/kg是否足够安全和耐受性，以及是否具有经过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变1型(HSAN1型)的III阶段试验中有理由进一步研究。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。我们最近发现了两种新的脱氧鞘磷脂(DSL)，它们聚集在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。两个新发现的DSL，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，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，我们已经证明，人类和小鼠的DSL水平可以通过补充这种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，我们将招募20名甲型HSAN1患者，其中10名受试者被分配给L丝氨酸(400 mg/kg/d)，10名受试者被分配给安慰剂，每人治疗1年，然后所有参与者交叉服用L丝氨酸1年。 药代动力学研究将在第一年和第二年开始进行，使我们能够完成两个PK系列，基线的安慰剂提供关于DSL水平的昼夜模式的信息，而一年的有效组在稳定的背景上提供关于L-丝氨酸的PK的信息。此外，我们将确定长期降低DSL水平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分量表、神经生理指标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第三阶段试验的最佳结果衡量标准。

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.