Chronic Obstructive Pulmonary Disease


Advances in the Treatment of Alpha1-antitrypsin Deficiency Jorge Lascano, Matthias Salathe and Michael Campos


Division of Pulmonary, Critical Care and Sleep Medicine, Miller School of Medicine, University of Miami


Abstract


Alpha1-antitrypsin deficiency (AATD) is an autosomal co-dominant condition characterised by low circulating levels of Alpha1-antitrypsin (AAT) and the accumulation of polymerised AAT molecules in the hepatocyte. Patients with this condition are susceptible to developing chronic lung and liver disease. Lung disease occurs in part from loss of neutrophil elastase inhibition and liver disease from a gain-of-toxic function and endoplasmic reticulum stress in hepatocytes. The pro-inflammatory nature of AAT polymers likely contributes to disease pathogenesis. New therapeutic efforts are being developed targeting specific pathophysiology mechanisms of the disease. These include increasing circulating AAT levels above the current therapeutic target with higher doses of intravenous AAT or by direct administration to the lung via the inhaled route. Other efforts include gene therapy and development of strategies to decrease the intracellular accumulation of AAT polymers by enhancing cellular degradation mechanisms, using chemical chaperones to target protein misfolding and designing molecules that can act as blockers of AAT polymerisation.


Keywords Alpha1-antitrypsin, alpha1-antitrypsin deficiency, treatment


Disclosure: Michael Campos has received research grants from Talecris Biotherapeutics, CSL Behring, the Alpha-1 Foundation and the National Institutes of Health. Jorge Lascano and Matthias Salathe have no conflicts of interest to declare. Received: 16 September 2010 Accepted: 28 March 2011 Citation: European Respiratory Disease, 2011;7(2):122–6 Correspondence: Michael Campos, RMSB (R-47) Room 7043 A, 1600 NW 10TH Ave, Miami, FL, 33140, US. E: mcampos1@med.miami.edu


Alpha1-antitrypsin deficiency (AATD) affects approximately 3.4 million individuals worldwide when individuals with the most common


abnormal Alpha1-antitrypsin (AAT) gene allele combinations (ZZ, SZ, or SS) are included.1


Clinically, AATD causes chronic obstructive


pulmonary disease (COPD) in adults and progressive liver disease in infants and adults.2,3


More recent observations also associate


abnormal AAT alleles with pulmonary and liver malignancies.4,5 Homozygous Z mutations occur in approximately 1 in 4,000–5,000 persons in the US6


and in about 1–2 % of subjects with COPD.7,8


Several efforts are under way to increase both awareness and effective therapeutic alternatives for this condition. Under-recognition of AATD as a cause of COPD has led to significant delays in its diagnosis,9,10


This article will address the new advances and future directions in the treatment of patients with AATD with emphasis in the pathophysiological mechanisms of disease, in particular AAT polymerisation, inflammation and protease-antiprotease imbalance. These therapies include augmentation therapy with purified AAT, gene therapy, inhaled AAT therapy, stem cell and bone marrow transplant, and therapies aimed at blocking AAT polymerisation.


Pathophysiology of Alpha1-antitrypsin Deficiency In order to better understand the rationale of potential therapeutic


mostly due to misconceptions by clinicians regarding its prevalence, age of presentation, association with smoking, race and distribution of emphysema. Not uncommonly, clinicians stereotype the presentation of AATD in young (<40 years of age) Caucasian non-smokers who present with COPD with predominantly lower-lobe emphysema. However, more than 80 % of patients have a significant smoking history and about one-third of affected subjects present with a more indolent presentation and are diagnosed after 50 years of age.10,11


upper-lobe emphysema.12


In addition, up to one-third have a predominantly These observations reflect significant


variations in the natural history of the pulmonary manifestations of AATD, likely influenced by both environmental exposure and genetic background. For this reason, current guidelines recommend AAT testing for all individuals who present with incompletely reversible airflow obstruction (COPD, bronchiectasis) as well as all individuals with unexplained liver disease.13


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AAT is an acute phase reactant and its major function is the neutralisation of serine proteases such as neutrophil elastase (NE). Like other serine protease inhibitors (serpins), the function of AAT depends on a unique conformational structure.16


approaches for AATD, it is important to briefly review the functions of AAT and the pathophysiology of the disease. AAT is a glycoprotein synthesised mostly by liver cells, although local synthesis also occurs by cells such as neutrophils, monocytes, macrophages, and epithelial cells.14,15


and AAT regulates immunologic responses. For example, AAT modulates endotoxin-induced inflammation,20 necrosis factor (TNF)-induced lung injury in rabbits,21 production by neutrophils22 to pro-inflammatory stimuli.23,24


Several recent observations suggest other non-canonical properties of AAT. AAT can protect endothelial cells from apoptosis by binding to caspases17–19


reduces tumour inhibits superoxide


and regulates the response of macrophages In addition, AAT may have a role in


regulating airway epithelial lining fluid balance by associating with important regulators such as matryptase.25


The loss of these effects in AATD may further contribute to the development of disease. © TOUCH BRIEFINGS 2011


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