UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Developing antisense oligonucleotide therapy for SPTLC1-related sensory neuropathy

Supervisors: Dr Haiyan Zhou, Professor Francesco Muntoni


Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a debilitating, progressive disorder of peripheral nerve that results in sensory loss, neuropathic pain, varying degrees of limb weakness, and mutilating skin ulceration severe enough to cause infection and warrant limb amputation. The disease is commonly caused by missense mutations in the SPTLC1 gene, which encodes for enzyme serine palmitoyltransferase (SPT). Very recently, mutations in SPTLC1 have also been reported in childhood onset amyotrophic lateral sclerosis. Mutations in SPTLC1 reduce the affinity of the enzyme for L-serine and increase its affinity for alanine and glycine, thereby leading to formation of an atypical class of neurotoxic 1-deoxysphingolipids. No effective treatment is currently available.  

Dr Zhou and Prof Muntoni’s laboratories have been leading in the preclinical and clinical development of nucleic acid therapies in genetic disorders, including neuromuscular and neurodegenerative disorders [1-3]. They have been working on developing antisense oligonucleotide therapy for SPTLC1-related HSAN1. An antisense approach has been designed to target an UK founder mutation in SPTLC1 gene. Zhou’s lab has been validating this ASO approach in vitro in different cellular models carrying the UK founder mutation. A partially humanized mouse model, carrying part of human SPTLC1 gene and the target mutation, is currently being developed in Zhou’s lab, for the in vivo validation of the ASO therapeutic approach.


1) The characterization of a humanized mouse model.

2) The in vivo validation of the ASO approach in transgenic mice.   


1.  Profiling the expression of human SPTLC1 transgene at mRNA and protein levels by quantitative real-time PCR and immunoblotting, and general histopathology studies in the key organs in wild-type and mutant mice. 

2.  SPT activity assay in different organs [4]. 

3. Histopathology studies in the Dorsal root ganglia (DRG), sciatic nerve and nerve ends in skin, and on markers of neurodegeneration in wild-type and mutant mice [5]. 

4. Pilot in vivo studies of therapeutic ASOs on specifically silencing the mutant transcripts and restoration of those altered biomarkers in the humanized mouse model. We will test different therapeutic regimen by comparing delivery methods between systemic and central nervous injections. 

Timeline (if applicable): 

Year 1-2: Characterization of the new mouse model. Personal license training (if applicable). 

Year 2-3: In vivo study of ASO efficacy in the transgenic mouse model.


  1. Sardone et al. Molecules. 2017; 22:563 
  2. Aguti et al. Mol Ther Nucleic Acids. 2020; 21:205-216 
  3. Marrosu et al. Mol Ther Nucleic Acids. 2017; 8:416-27 
  4. Kannan et al. Bio Protoc. 2020 Jun 20;10(12):e3656 
  5. McCampbell et al. Hum Mol Genet. 2005;14:3507-21