Clinical trial NCT01733407
Conditions: Hereditary Sensory and Autonomic Neuropathy Type I
Keywords: inherited neuropathies
Sponsor: Massachusetts General Hospital
Start date: 2013-09-01; Completion date: 2017-07-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
In hereditary sensory and autonomic neuropathy type 1 (HSAN1) the investigators recently discovered the accumulation of two neurotoxic sphingolipids. It appears that these lipids arise as the mutant enzyme has a reduced affinity for its normal preferred substrate L-serine. The investigators now plan to perform a two year study of L-serine supplementation to correct the biochemistry and neurological disease in humans with HSAN1. In the course the investigators will also establish correlations between an existing neurological rating scale of sensory neuropathy and intraepidermal nerve fiber density.

Funding Source - FDA OOPD

Detailed description:
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. The investigators recently identified two novel deoxysphingoid bases (DSB) 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 the investigators have 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 cross over study the investigators 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 12 months. The 10 subjects assigned to placebo will then be crossed over to active L-serine for the remaining 12 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. L-serine levels will be measured using 24-hour pharmacokinetic blood sample at 12-month intervals. The investigators will assess the percentage of failures (clinical decline of \> 1 point on CMTNS or \> 30% decrease in IENFD) at 6 month intervals. Regardless of CMTNS score, all subjects who are on placebo for the first year will be switched to active study drug in year two.

After the 2 year period subjects will be given the option of being re-consented for the open label extension. All consented subjects will then be treated with L-serine (400 mg/kg/d) for an additional year.

Arms: arm 1: Placebo arm arm 2: amino acid supplementation with L-serine
Interventions: intervention 1: L-serine intervention 2: placebo
Intervention descriptions: intervention 1: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2. intervention 2: 400mg/kg/d divided TID for year 1 only.

Protocol documents: