Can Enzyme Replacement Therapy revert iNKT cell dysfunction in Acid Sphingomyelinase Deficiency patients?

Investigador: Fátima Macedo
PhD in Biomedical Sciences, Senior Researcher, Instituto de Investigação e Inovação em Saúde (i3S) in Porto University

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and neurological functions, with severe forms of the disease being fatal in the first years of life.

Invariant Natural Killer T (iNKT) cells are lipid-reactive T cells that play a central role in a wide range of immune responses, mainly through their high capacity of producing cytokines. iNKT cells are restricted to CD1d-presented lipid antigens, such as a-galactosylceramide, depending on the presentation of these molecules for normal activation and function. Sphingomyelin is a lipid with affinity for CD1d and its accumulation in ASMD influences the role of iNKT cells by impairing normal antigen presentation to these cells. Interestingly, ASM-/- mice have reduced number of iNKT cells, impaired iNKT cell activity and deregulated iNKT-cell dependent inflammation, while in ASMD patients a reduced frequency of iNKT cells is also observed. Noteworthy, enzyme replacement therapy (ERT) with recombinant ASM can prevent iNKT cell deficiency in ASM-/- mice.
Until recently, there were very limited treatment modalities for ASMD patients, with conservative approaches being the main option. ERT was recently authorized by the European Medicines Agency for non-central nervous system manifestations of ASMD, but Portuguese patients haven’t yet started to receive treatment. Therefore, we stand at a unique window of opportunity to study how ERT influences human iNKT cell activity. With this project, we expect to better understand whether the iNKT cell deficiency found in ASMD patients can be reverted by ERT and whether this therapeutic approach can induce phenotypic and functional changes in iNKT cells of ASMD patients.