Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a monogenic, autosomal dominantly inherited, neurodegenerative disorder resulting in loss of pain and temperature sensation in the distal limbs. HSAN1 is caused by point mutations in a single allele of serine palmitoyltransferase long chain base 1 (SPTLC1), resulting in production of neurotoxic deoxysphingolipids (dSLs). Oligonucleotide therapeutics (ONTs) can be used to downregulate the mutant allele and/or the wild type allele and thus are viable treatment strategies. We investigated the ability of two classes of ONTs, short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), to downregulate SPTLC1 in an in vitro model of HSAN1 derived from the C133W mouse model overexpressing mutant hamster SPTLC1. We screened a panel of siRNAs and ASOs targeting mutant hamster SPTLC1 and identified four lead compounds. We demonstrated these compounds’ ability to reduce mutant hamster SPLTC1 and/or wild type mouse SPTLC1 mRNA in CHO cells and C57BL/6J embryonic mouse primary cortical neurons. We then showed that these compounds downregulate hamster and mouse SPTLC1 mRNA and protein in embryonic primary cortical neuron cultures derived from C133W mice. These compounds demonstrate therapeutic potential and should be developed further in vivo.