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Author Affiliations
- UCL Respiratory, Division of Medicine, University College London, United Kingdom
Address correspondence to:
David Lomas, MD, PhD
UCL Respiratory, Division of Medicine
Rayne Building
University College London
WC1E 6BN
London, UK
Email: d.lomas@ucl.ac.uk
Abstract
Alpha-1antitrypsin deficiency (AATD) results from the intracellular polymerization and retention of mutant alpha-1antitrypsin (AAT) within the endoplasmic reticulum of hepatocytes. This causes cirrhosis whilst the deficiency of circulating AAT predisposes to early onset emphysema. This is an exciting time for researchers in the field with the development of novel therapies based on understanding the pathobiology of disease. I review here augmentation therapy to prevent the progression of lung disease and a range of approaches to treat the liver disease associated with the accumulation of mutant AAT: modifying proteostasis networks that are activated by Z AAT polymers, stimulating autophagy, small interfering RNA and small molecules to block intracellular polymerization, and stem cell technology to correct the genetic defect that underlies AATD.
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Katie M. Stiles, PhD1* Dolan Sondhi, PhD1* Stephen M. Kaminsky, PhD1 Bishnu P. De, PhD1 Jonathan B. Rosenberg, PhD1 Ronald G. Crystal, MD1
Author Affiliations
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Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
* KMS and DS contributed equally to this review
Address correspondence to:
Katie M. Stiles, PhD or
Dolan Sondhi, PhD
Department of Genetic Medicine
Weill Cornell Medical College
1300 York Avenue, Box 164
New York, New York 10065
Phone: (646) 962-4363
Fax: (646) 962-0220
E-mail: geneticmedicine@med.cornell.edu
Abstract
Alpha-1 antitrypsin deficiency (AATD) manifests primarily as early-onset emphysema caused by the destruction of the lung by neutrophil elastase due to low amounts of the serine protease inhibitor alpha-1 antitrypsin (AAT). The current therapy involves weekly intravenous infusions of AAT-derived from pooled human plasma that is efficacious, yet costly. Gene therapy applications designed to provide constant levels of the AAT protein are currently under development. The challenge is for gene therapy to provide sufficient amounts of AAT to normalize the inhibitor level and anti-neutrophil elastase capacity in the lung. One strategy involves administration of an adeno-associated virus (AAV) gene therapy vector to the pleural space providing both local and systemic production of AAT to reach consistent therapeutic levels. This review focuses on the strategy, advantages, challenges, and updates for intrapleural administration of gene therapy vectors for the treatment of AATD.
Citation
Citation: Stiles KM, Sondhi D, Kaminsky SM, De BP, Rosenberg JB, Crystal RG. Intrapleural gene therapy for alpha-1 antitrypsin deficiency-related lung disease. Chronic Obstr Pulm Dis. 2018; 5(4): 244-257. doi: http://dx.doi.org/10.15326/jcopdf.5.4.2017.0160
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Joseph E. Kaserman, MD1 Andrew A. Wilson MD1
Author Affiliations
- Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, Massachusetts
Address correspondence to:
Andrew A. Wilson, MD
Center for Regenerative Medicine
Boston University and Boston Medical Center
670 Albany St., 2nd Floor
Boston, MA 02118
Tel: 617-414-3282
Fax: 617-536-8093
Email: awilson@bu.edu
Abstract
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.
Citation
Citation: Kaserman JE, Wilson AA. Patient-derived induced pluripotent stem cells for alpha-1 antitrypsin deficiency disease modeling and therapeutic discovery. Chronic Obstr Pulm Dis. 2018; 5(4): 258-266. doi: http://dx.doi.org/10.15326/jcopdf.5.4.2017.0179
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Boris M. Baranovski, MSc1 Ronen Schuster, PhD1 Omer Nisim, BLabMed1 Ido Brami, BMedSci1 Yotam Lior, BMedSci1 and Eli C. Lewis, PhD1
Author Affiliations
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Address correspondence to:
Eli C. Lewis, PhD
Department of Clinical Biochemistry & Pharmacology
Faculty of Health Sciences
Ben-Gurion University of the Negev
POB 151, Be’er-Sheva 8410501, Israel
Phone: ++972-8-6244-574
e-mail: lewis@bgu.ac.il
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder which most commonly manifests as pulmonary emphysema. Accordingly, alpha-1 antitrypsin (AAT) augmentation therapy aims to reduce the progression of emphysema, as achieved by life-long weekly slow-drip infusions of plasma-derived affinity-purified human AAT. However, not all AATD patients will receive this therapy, due to either lack of medical coverage or low patient compliance. To circumvent these limitations, attempts are being made to develop lung-directed therapies, including inhaled AAT and locally-delivered AAT gene therapy. Lung transplantation is also an ultimate therapy option. Although less common, AATD patients also present with disease manifestations that extend beyond the lung, including vasculitis, diabetes and panniculitis, and appear to experience longer and more frequent hospitalization times and more frequent pneumonia bouts. In the past decade, new mechanism-based clinical indications for AAT therapy have surfaced, depicting a safe, anti-inflammatory, immunomodulatory and tissue-protective agent. Introduced to non-AATD individuals, AAT appears to provide relief from steroid-refractory graft-versus-host disease, from bacterial infections in cystic fibrosis and from autoimmune diabetes; preclinical studies show benefit also in multiple sclerosis, ulcerative colitis, rheumatoid arthritis, acute myocardial infarction and stroke, as well as ischemia-reperfusion injury and aberrant wound healing processes. While the current augmentation therapy is targeted towards treatment of emphysema, it is suggested that AATD patients may benefit from AAT augmentation therapy geared towards extrapulmonary pathologies as well. Thus, development of mechanism-based, context-specific AAT augmentation therapy protocols is encouraged. In the current review, we will discuss extrapulmonary manifestations of AATD and the potential of AAT augmentation therapy for these conditions.
Citation
Citation: Baranovski BM, Schuster R, Nisim O, Brami I, Lewis EC. Alpha-1 antitrypsin substitution for extrapulmonary conditions in alpha-1 antitrypsin deficient patients. Chronic Obstr Pulm Dis. 2018; 5(4): 267-276. doi: http://dx.doi.org/10.15326/jcopdf.5.4.2017.0161
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Félix-Antoine Vézina, MD1 André M. Cantin, MD1,2
Author Affiliations
- Respiratory Division, Department of Medicine, Faculty of Medicine and Health Sciences, University of Sherbrooke, Quebec Canada
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Quebec, Canada
Address correspondence to:
André M. Cantin, MD
Pulmonary Research Unit
Faculty of Medicine, University of Sherbrooke
3001, 12ième Avenue Nord, Fleurimont, QC
Canada J1H 5N4
Phone number: 819-346-1110 ext. 14893
Email: Andre.Cantin@USherbrooke.ca
Abstract
Antioxidants represent an attractive therapeutic avenue for individuals with chronic obstructive pulmonary disease (COPD). Cigarette smoke, the major cause of COPD, contains very high concentrations of gaseous and soluble oxidants that can directly induce cell injury and death. Furthermore, particulate matter in cigarette smoke activates lung macrophages that subsequently attract neutrophils. Both neutrophils and macrophages from the lungs of cigarette smokers continuously release large amounts of superoxide and hydrogen peroxide through the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Once individuals with COPD stop smoking, the neutrophilic inflammation in the airways and lung parenchyma persists, as do the markers of oxidative stress. Several animal models of cigarette smoke-induced injury have provided evidence that various antioxidants may prevent inflammation and morphological changes associated with COPD however, evidence of benefit in patients is less abundant. Although oxidants can inactivate alpha-1 antitrypsin and other protective proteins, damage lung tissue, and increase mucus production, they also are essential for killing pathogens and resolving inflammation. This review will examine the pre-clinical and clinical evidence of a role for antioxidants in the therapy of patients with COPD.
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Author Affiliations
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville
Address correspondence to:
Sihong Song, PhD
Department of Pharmaceutics
College of Pharmacy University of Florida
Gainesville, FL 32610
Email: shsong@ufl.edu
Phone: 352-273-7867
Abstract
Autoimmune diseases are conditions caused by an over reactive immune system that attacks self-tissues and organs. Although the pathogenesis of autoimmune disease is complex and multi-factorial, inflammation is commonly involved. Therefore, anti-inflammatory therapies hold potential for the treatment of autoimmune diseases. However, long-term control of inflammation is challenging and most of the currently used drugs have side effects. Alpha-1 antitrypsin (AAT) is an anti-inflammatory protein with a well-known safety profile. The therapeutic potential of AAT has been tested in several autoimmune disease models. The first study using a recombinant adeno-associated viral (rAAV) vector showed that AAT gene transfer prevented the development of type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. Subsequent studies showed that treatment with AAT protein prevented and reversed type 1 diabetes. The beneficial effects of AAT treatment have also been observed in other autoimmune disease models such as rheumatoid arthritis and systemic lupus erythematosus. This paper reviews the therapeutic application of AAT and discusses possible mechanisms of action in various autoimmune diseases.
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