Modeling Wolman disease using genetically engineered human liver organoids

Wolman disease (WD) is a rare disease caused by mutations in the lysosomal acid lipase (LIPA) gene, whose protein product is responsible for the breakdown of different lipids within liver cells. This genetic disease is a severe disorder that presents during infancy and with an average life expectancy of less than 4 months. WD-associated deaths rely on pervasive hepatic cell degeneration and consequent liver failure caused by the accumulation of intracellular toxic lipids. Unfortunately, no specific drugs are currently available in the market, making this rare disorder largely untreatable. The lack of experimental models able to faithfully mirror different aspects of WD progression is currently considered the major cause of the lack of therapeutic protocols to treats WD.
Based on this ground, this project proposes the development an innovative model of WD using the innovative human “mini-liver” culture technology, in order to obtain tangible clinical benefit for patients suffering of this devastating disease. To this aim, an unprecedented 3D cell culture system, able to recapitulate the entire spectrum of WD-associated clinical traits, will be developed. This new technology will be used to unveil novel mechanisms of WD progression, as well as to test, in parallel, hundreds of drug for their efficacy in counteracting WD-associated cellular defects.
In sum, this project explores a medical relevant concept and proposes cutting edge methodologies, while remaining feasible in light of past scientific contribution of the applicant, his peculiar expertise and the solid preliminary results.