Acid sphingomyelinase deficiency (ASMD) or
Niemann-Pick disease type A (NPA), type B (
NPB) and type A/B (NPA/B), is a rare
lysosomal storage disease characterized by progressive accumulation of
sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a
NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered
lipid homeostasis in the patient-derived organoids showing the predictable increase in
sphingomyelin (SM), together with
cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in
phosphatidylcholine (PC) and
cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of
enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and
glycoproteins, as well as upregulated genes coding for different
glycosidases and
cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.