Mechanistic convergence and shared therapeutic targets in Niemann-Pick disease.

Abstract

Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.

• Authors: Alexandria Colaco, Ecem Kaya, Elias Adriaenssens, Lianne C Davis, Stefania Zampieri, María E Fernández-Suárez, Chong Y Tan, Patrick B Deegan, Forbes D Porter, Antony Galione, Bruno Bembi, Andrea Dardis, Frances M Platt
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 43 Issue 3 Pg. 574-585 (05 2020) ISSN: 1573-2665 [Electronic] United States
• PMID: 31707734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• Intracellular Signaling Peptides and Proteins
• NPC1 protein, human
• Niemann-Pick C1 Protein
• 1-Deoxynojirimycin
• miglustat

Topics

• 1-Deoxynojirimycin (analogs & derivatives, therapeutic use)
• ATP Binding Cassette Transporter 1 (genetics)
• Adult
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Middle Aged
• Niemann-Pick C1 Protein
• Niemann-Pick Disease, Type C (drug therapy, genetics)
• Treatment Outcome