Patient-Derived Induced Pluripotent Stem Cells for Alpha-1 Antitrypsin Deficiency Disease Modeling and Therapeutic Discovery.

PIZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disease affecting approximately 100,000 individuals in the United States and one of the most common hereditary causes of liver disease.¹ The most common form of the disease results from a single base pair mutation (Glu342Lys), known as the "Z" mutation, that encodes a mutant protein (Z alpha-1 antritypsin [AAT]) that is prone to misfolding and is retained in the endoplasmic reticulum (ER) rather than appropriately secreted. Some of the retained mutant protein attains an unusual aggregated or polymerized conformation. Retained polymeric ZAAT aggregates are hepatotoxic and lead to downstream liver disease in a subset of PiZZ neonates and adults through a gain-of-function mechanism. PiZZ individuals are likewise highly predisposed to developing chronic obstructive pulmonary disease (COPD)/emphysema as a result of low circulating levels of AAT protein and associated protease-antiprotease imbalance. Much of our understanding of the molecular pathogenesis of AATD is based on studies employing either transgenic mice that express the mutant human Z allele or immortalized cell lines transduced to overexpress ZAAT. While they have been quite informative, these models fail to capture the patient-to-patient variability in disease phenotype that clinicians observe in their AATD patients, raising the question of whether alternative models might provide new insight. Induced pluripotent stem cells (iPSCs), first described in 2006, have the capacity to differentiate into a broad array of cell types from all 3 germ layers, including hepatocytes. Disease-specific iPSCs have been derived from patients with a variety of monogenic disorders and have been found to faithfully recapitulate features of such diseases as spinal muscular atrophy, familial dysautonomia, Rett syndrome, polycythemia vera, type 1A glycogen storage disease, familial hypercholesterolemia, long QT syndrome, and others. This discussion reviews the potential applications of iPSCs for understanding AATD-associated liver disease as well as for development of potential therapeutic strategies.