Since the discovery of disease-causing mutations in genes coding for the serine palmitoyltransferase (SPT) subunits SPTLC1 and SPTLC2, much progress has been made in understanding the underlying pathophysiology of hereditary sensory and autonomic neuropathy type I (HSAN-I). Dominant mutations in SPTLC1 and SPTLC2 influence the substrate specificity of the SPT enzyme leading to the formation of toxic deoxysphingolipids. Indeed, the mutant enzyme prefers to metabolise L-alanine or L-glycine instead of its natural substrate L-serine. The formation of neurotoxic deoxysphingolipids induce axonal degeneration in vitro and in vivo. Providing an excess of L-serine, and thereby reducing the relative abundance of L-alanine/L-glycine, was shown to reduce the formation of toxic deoxy-sphingolipids. Encouragingly, these findings were successfully translated from animal models to HSAN-I patients as demonstrated by a recent clinical trial on high-dose L-serine supplementation. However, two downsides of the L-serine supplementation therapy remain unsolved. On one hand, patients need to take very high doses of L-serine on a daily basis in order to maintain the suppressing effect. Secondly, while the treatment is effective in countering the neurodegeneration, it does not rescue the HSAN-I-associated immunodeficiency. In fact, patients on L-serine treatment even show a trend towards more immunological complications. We have preliminary results demonstrating that sphinganine supplementation was able to correct the CD8+ T cell deficiency in HSAN-I patients. This may therefore form a potent, yet simple, therapy which can rescue the T cell-intrinsic defects associated with HSAN-I. Whether sphinganine also provides beneficial effects for the peripheral nervous system remains to be tested. This PhD project therefore aims to investigate if additional supplementation with sphinganine could be beneficial to HSAN-I patients. To this end, we will develop human induced pluripotent stem cells (hiPSC) from HSAN-I patients with a SPTLC1 and SPTLC2 mutation. From the iPSC lines we will generate sensory neurons through optimization of an established protocol. These sensory neuron cultures will be supplemented with sphinganine and/or L-serine to assess their potency on rescuing the neurodegenerative phenotype. In addition, a transcriptomic analysis will be performed on CD8+ T cells treated with either sphinganine or L-serine to profile the underlying molecular differences related to T cell intrinsic defects and potentially identify other therapeutic options for ulcero-mutilating neuropathies.