Apolipoprotein A-I Mimetics for the Treatment of Niemann-Pick Disease
Fawaz, Maria
2020
Abstract
Niemann-Pick disease (NPD) is a fatal lipid storage disorder that results in an accumulation of unesterified cholesterol (type C) or sphingomyelin (types A and B) in late endosomes and lysosomes. Inherited defects in NPC1 or NPC2 genes are responsible for NPD type C (NPC) while mutations in SMPD1 gene cause NPD types A (NPA) and B (NPB). To date, NPD management is largely symptomatic with only few therapies in clinical trials. Therefore, the main objective of this dissertation was to develop safe and effective therapeutics for the treatment of NPA/B and NPC. In NPD, the defects in cholesterol and sphingomyelin metabolism cause a panel of cellular problems including markedly decreased levels of high-density lipoproteins (HDL) responsible for the extracellular lipid transport. The body produces HDL as an 8-12 nm nanoparticle composed of a lipid membrane wrapped around by a belt of Apolipoprotein A-I (ApoA-I). Several synthetic HDL (sHDL) particles made of ApoA-I or ApoA-I mimetic peptides complexed with various phospholipids have been previously tested in patients for the treatment of atherosclerosis, where sHDL has been found safe at doses up to 100 mg/kg following intravenous administration. Applying the same strategy to NPD, we proposed that ApoA-I mimetics (peptide or sHDL) could be effective and rapidly translatable therapeutic approaches for the treatment of NPD. In the second chapter, we investigated the therapeutic potential of ApoA-I mimetic peptides and sHDL in NPC. Nanoparticles, particularly 5A-SM sHDL, were effective at reducing cholesterol accumulations in human NPC cells and resulted in the rescue of peripheral disease with intraperitoneal route in NPC1 mice. However, the correction of motor function was not detected. A direct brain administration of sHDL reduced cholesterol storage in neurons of NPC1 mice suggesting that the alternative delivery routes, treatment durations, or sHDL composition were still needed to be investigated. In the third chapter, we used a similar strategy to NPC. We identified a peptide, 22A, and sHDL capable of reducing sphingomyelin levels in human NPA cells. Moreover, the ATP-binding cassette A1 transporter was found to be involved in sphingomyelin efflux from cells. Intravenous administration of 22A to wild type mice rapidly mobilized sphingomyelin from tissues into circulation. In addition to sphingomyelin, peptide and sHDL could both mobilize cholesterol, which was found to be elevated in NPA disease. Together, our data showed that ApoA-I mimetics might represent a novel therapeutic approach for NPA disease. In the fourth chapter, we systematically evaluated the effect of both peptide sequence and phospholipid composition of sHDL on nanoparticle’s ability to mobilize and esterify cholesterol in vitro and in vivo. Historically, sHDL drug discovery efforts were mainly focused on optimizing peptide sequences rather than understanding how both, peptide and lipid, influence sHDL pharmacokinetic and pharmacodynamic profiles. Two sets of sHDL were designed having either identical phospholipid but variable peptide sequences with different plasma stability, or identical peptide and phospholipids with variable fatty acid chain length and saturation. The results indicated that the phospholipid component in sHDL played a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. In conclusion, the findings from these studies provide a solid foundation for the future development of ApoA-I mimetic peptides and sHDL for the treatment of Niemann-Pick disease.Subjects
Apolipoprotein A-I mimetics Niemann-Pick disease High-density lipoprotein Cholesterol trafficking Sphingomyelin
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