Research projects

Of the nearly 8,000 diseases classified as rare diseases (RDs), between 4,000 and 5,000 lack any form of treatment. The limited number of patients who could benefit from a specific therapy, combined with the need for an exhaustive characterization of the molecular consequences of genetic variants, have been key factors in explaining the pharmaceutical industry's historically low interest in these conditions. Currently, the growing investment in protein engineering, RNA technology and gene editing is driving increased interest from the pharmaceutical industry in diseases with high mortality rates and no effective therapy. One such condition is PMM2-CDG, an autosomal recessive genetic disorder caused by a deficiency in phosphomannomutase 2 (PMM2), a cytosolic enzyme that catalyses the conversion of mannose-6P to mannose-1P, the first step in the protein glycosylation pathway. PMM2-CDG is a multisystemic disease characterized by severe neurological impairment and cerebellar atrophy.

In this project, we propose combining the targeted delivery of different drugs using biocompatible nanoformulations designed to reach the liver, as well as nanocarriers capable of crossing the blood-brain barrier. The study will follow a multi-step validation cascade, starting with PMM2 knockout cellular models generated via gene editing, followed by validation in patient-derived fibroblasts and ultimately in hepatocytes, Purkinje cells, and cerebral organoids derived from hiPSC (human-induced pluripotent stem cells) from PMM2-CDG patients. In these models, we will assess the restoration of PMM2 activity as well as the recovery of affected cellular processes through the analysis of epigenetic, transcriptomic, and glycoproteomic signatures. Finally, we will evaluate the therapeutic effect and biodistribution in a murine model of PMM2-CDG.