L-Serine Study Results

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DELAYED-START TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF L-SERINE IN SUBJECTS WITH HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1 (HSAN1)

Vera Fridman1, Peter Novak2, William David3, Anne Louise Oaklander3, Eric Macklin3, Diane McKenna-Yasek2, Kailey Walsh3, Robert Brown2, Thorsten Hornemann4, Florian Eichler3  1University of Colorado Medical Center, Denver, US., 2University of Massachusetts Medical School, Worcester, US.,3 Massachusetts General Hospital (MGH), Boston, US., 4University Hospital Zurich, Clinical Chemistry, Zurich, Switzerland.

Introduction: Hereditary Sensory Autonomic Neuropathy Type 1 (HSAN1) is a severe, autosomal dominant, axonal neuropathy that manifests with marked, small fiber predominant sensory loss, variable degrees of limb weakness, and skin ulceration. HSAN1 is caused by mutations in the SPTLC1 and SPTLC2 genes, which encode two of the three subunits of the enzyme serine palmitoyltransferase (SPT). Mutations in SPT induce a permanent shift in the substrate preference from serine to alanine thereby forming a class of neurotoxic deoxysphingolipids (dSL). Supplementation with L-serine reduces dSL levels in transgenic HSAN1 mice and results in clinical improvement of neuropathy. We report a two-year, delayed-start, placebo-controlled clinical trial evaluating the safety and efficacy of oral L-serine (400 mg/kg/d) in human subjects with HSAN1.

Results: All but 2 subjects (both of whom

Continue Reading →

Research Funded by the Deater Foundation

We​ ​are​ ​very​ ​pleased​ ​to​ ​provide​ ​this​ ​update​ ​on​ ​progress​ ​toward​ ​devising​ ​methods​ ​to silence​ ​the​ ​SPTLC1​ ​gene​ ​as​ ​a​ ​potential​ ​therapy​ ​for​ ​HSAN1.​ ​We​ ​have​ ​made​ ​progress in​ ​three​ ​areas.​ ​​ ​The​ ​key​ ​point​ ​is​ ​that​ ​we​ ​have​ ​now​ ​developed​ ​two​ ​types​ ​of​ ​reagents that​ ​can​ ​silence​ ​the​ ​SPTLC1​ ​gene.  
  
One​ ​type​ ​of​ ​reagent​ ​is​ ​composed​ ​of​ ​small​ ​strings​ ​of​ ​~​ ​20​ ​molecules​ ​of​ ​nucleic​ ​acids (antisense​ ​oligonucleotides​ ​or​ ​ASO’s)​ ​that​ ​have​ ​sequences​ ​complementary​ ​to​ ​specific sequences​ ​in​ ​the​ ​SPTLC1​ ​gene.​ ​​ ​The​ ​concept​ ​is​ ​that​ ​these​ ​ASO’s​ ​bind​ ​RNA​ ​from​ ​the​ ​target​ ​gene​ ​and thereby​ ​activate​ ​enzymes​ ​that​ ​break-up​ ​the​ ​RNA,​ ​preventing​ ​it​ ​from​ ​making​ ​protein.​ ​​ ​​ ​As​ ​we​ ​have reported​ ​before,​ ​we​ ​have​ ​been​ ​fortunate​ ​to​ ​have​ ​Havisha​ ​Karnam​ ​as​ ​a​ ​graduate​ ​student​ ​working​ ​in conjunction​ ​with​ ​Anastasia​ ​Khvorova​ ​Ph.D.​ ​on​ ​this​ ​project.​ ​​ ​Dr.​ ​Khvorova​ ​is​ ​an​ ​internationally recognized​ ​expert​ ​in​ ​the​ ​chemistry​ ​of​ ​ASO’s.​ ​​ ​With​ ​Dr.​ ​Khvorova’s​ ​guidance,​ ​Havisha​ ​has​ ​used​ ​two types​ ​of​ ​chemistry​ ​(designated​ ​LNA​ ​gapmers​ ​and​ ​hsiRNA)​ ​to​ ​generate​ ​ASO’s​ ​that​ ​can​ ​silence SPTLC1.​ ​​ ​In​ ​particular,​ ​she​ ​has​ ​developed​ ​ASO’s​ ​that​ ​specifically​ ​target​ ​hamster​ ​SPTLC1​ ​and​ ​not mouse,​ ​and​ ​reciprocally.​ ​​ ​She​ ​also​ ​now​ ​has​ ​ASO’s​ ​that​ ​target​ ​human​

Continue Reading →