Phase 2 Study of L-Serine in HSN Type 1

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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.