Drug testing for liver disease in alpha-1 antitrypsin deficiency by a large-scale patient-specific hiPS cells library

A1-antitrypsin deficiency (ATD) is an inherited disorder where an abnormal α1-antitrypsin (AAT) protein is produced by liver cells. Multiple genetically mutated forms of AAT exist, but only a few produce the pathology in the liver, where the protein aggregates and accumulates causing cell death and ultimately cirrhosis. However, many patients having the "pathologic" form of AAT do not develop the disease. Currently, no medical treatment is recommended for ATD-related liver diseases, but a few drugs (used for other diseases) have been proposed that either enhance AAT secretion from liver cells into the circulation, where the protein normally plays its role, or induce protein degradation. However, given the apparent variability in the pathological outcome between patients, a large-scale systematic drug screening of efficacy is required. During this two-year project, we will produce a library of patient-specific blood- or urine-derived liver cells of almost all the genetic variants causing the severe form of the disease and some causing the mild form within the Italian Registry for ATD, including also patients that did not show pathological signs even with a genetic "pathologic" form of AAT; we will use this library to evaluate how drugs already on the market for other pathologies can reduce AAT accumulation in liver cells and be proposed for ATD therapy; and we will use a subgroup of the 5 most promising drugs for determining their therapeutic efficacy and dosage in almost all the known pathological AAT-variant patients.