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

描述（由申请人提供）：研究目的是确定400mg /kg/天口服l -丝氨酸是否足够安全和耐受，并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变1型（HSAN1）的III期试验中进一步研究的合理性。遗传性感觉和自主神经病变I型（HSAN1）是一种进行性和衰弱性疾病，目前尚无治疗方法。我们最近在HSAN1患者和转基因HSAN1突变小鼠的血浆中发现了两种新的脱氧鞘脂（dSL）。这种疾病是由编码丝氨酸棕榈酰转移酶（SPT）亚基的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与丝氨酸反应形成鞘氨酸。两种新发现的dSL，脱氧鞘氨氨酸和脱氧甲基鞘氨氨酸，分别是由棕榈酰辅酶a与丙氨酸和甘氨酸缩合产生的，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，人类和小鼠体内的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、安慰剂对照的研究中，我们将招募20名患有HSAN1的研究参与者，其中10名受试者分配给l -丝氨酸（400mg/kg/d）， 10名受试者分配给安慰剂，每人治疗1年，随后所有参与者交叉使用l -丝氨酸再治疗1年。

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.