Phospholipid nanoparticles for lipase deficiency gene replacement therapy
Matthias Zadory (PhD fellow sponsored by the PRC) - Faculty of Pharmacy, University of Montréal, Canada
The recent approval of a phospholipid nanoparticle-based genetic medicine highlights the potential value of the approach. Here, we will investigate its potential in the treatment of lipid metabolism-associated disorders, for which metabolic alterations are key factors contributing to the pathogenesis, by designing a new phospholipid-based pharmaceutical formulation. We will design nanoparticles consisting of biocompatible lipids loaded with genetic material to restore the loss of metabolic lipases, enzymes critically involved in lipid metabolism. Their deficiency generates an imbalance in lipid catabolism and accumulation of lysosomal cholesteryl esters and triglycerides, especially in hepatocytes and macrophages, leading to severe diseases.1) 2) Advanced in vitro cell biology and lipidomic methods will be used to determine the effects of the particles on a potential improvement of lipid metabolism. The project will likely open new horizons for the treatment of other genetic and metabolic disorders associated with dysfunction of lipid metabolism.
Benefit for the community
Overall, this project has two main objectives: i) develop a library of lipid nanoparticles (LNPs) to give diseased cells the ability to generate highly functional enzymes; and ii) design a technology platform that could be applied to other genetic diseases. This project will enable the discovery of the key parameters influencing the functionality of these LNPs and the identification of the best performing ones. The same concept could be applied to other conditions/disorders where the liver can be converted into a “protein factory” to improve lipid metabolism.
Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants
Atherosclerosis 265, 124-132
Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency
Lancet Gastroenterol. Hepatol. 2, 670-679