Alpha-1 Antitrypsin Deficiency: Recent Developments in Gene Therapy Research.
Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder associated with mutations in the SERPINA1 gene (Kelly et al., 2008; Greene et al., 2008). Over 100 different alleles have been identified however the most common disease-causing mutation, termed Z, encodes a glutamic acid to lysine substitution at position 342 of the mature AAT protein. As a member of the serine proteinase inhibitor family, the role of AAT is to inhibit serine proteases throughout the body but principally in the lung. The ZAAT protein fails to adopt the correct protein conformation and polymerises and accumulates intracellularly in AAT-producing cells. The liver is the major source of the body’s pool of AAT. The major consequences of ZAAT accumulation in hepatocytes are toxic gain of function events leading to endoplasmic reticulum (ER) expansion and dilation and activation of multiple ER stress signalling pathways (Lomas et al., 1992; Teckman & Perlmutter, 2000; Lawless et al., 2004; Hidvegi et al., 2005; Hidvegi et al., 2007; Miller et al., 2007). These predispose to liver failure. The second major clinical consequence of ZAAT deficiency is a lower than normal antiprotease protective screen throughout the body, but most importantly in the lung (Lomas et al., 1993). ZAAT deficient individuals can develop emphysematous lung disease as early as in their 4th decade. Gene therapies to treat both aspects of the disease are currently at various stages of development. For the liver disease approaches that can be considered include ribozymes, antisense, peptide nucleic acids and small-interfering RNAs; all designed to inhibit expression of the mutant gene (recently reviewed in McLean et al., 2009). For the lung disease gene therapies using non-viral, lentiviral and adeno-associated viral approaches to express the normal gene either locally or intramuscularly have been reported (Chulay et al., 2011; Brantly et al., 2006; Flotte et al., 2007; Argyros et al., 2008; Brantly et al., 2009; Liqun Wang et al., 2009); all aim to increase AAT levels in the circulation above the deficiency threshold of 11 μM. New approaches are focused on coupling haematopoietic stem cell therapy with AAT-lentiviral gene therapy (Ghaedi et al., 2010; Argyros et al., 2008). This chapter will review the history and current state-of-the-art in these areas.