L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1
| Status: | Completed |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/14/2018 |
| Start Date: | September 2013 |
| End Date: | July 2017 |
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of L-Serine in Subjects With Hereditary Sensory Neuropathy Type 1
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
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
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.
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.
Inclusion Criteria:
- HSAN1 patients with prominent sensory loss with foot ulcers or shooting pains and
con-firmed mutations in SPTLC1.
- Males and females of 18 years or older
- All patients will be able to provide informed consent and comply with oral dietary
supple-mentation and study activities. Compliance with supplementation will be
monitored through measurement of DSB levels.
- Subjects must not have taken L-serine for at least 30 days prior to randomization
(L-serine-naïve subjects are permitted in the study).
- Women must not become pregnant for the duration of the study and must be willing to
use two contraceptive therapies and have a negative pregnancy test throughout the
course of the study.
Exclusion Criteria:
- Any cause of neuropathy other than HSAN1 (such as diabetes or drug-induced
neuropathy), medical history of kidney stones, or history of poliomyelitis or
radiotherapy.
- Pregnant women, breastfeeding, or not using adequate contraception; for women
included, an accepted method of contraception will be used throughout the study.
- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.
- Patients on blood-thinners such as warfarin (Coumadin) or heparin will not be biopsied
until they have held the medication for 5 days. Following the biopsy they will resume
the maintenance dose of their medication.
- Serious illness (requiring systemic treatment and/or hospitalization) until subject
either completes therapy or is clinically stable on therapy, in the opinion of the
site investigator, for at least 10 days prior to study entry.
- The presence of unstable psychiatric disease, cognitive impairment, or dementia that
would impair ability of the subject to provide informed consent, according to PI
judgment, or a history of active substance abuse within the prior year.
- Subjects who are non-ambulatory.
- Subjects with uncontrolled diabetes.
- Patients who are unable or unwilling to give consent will not be enrolled in the
study.
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