The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy: A Pilot Study.

CONCLUSION: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01669421. PMID: 30965011 [PubMed - as supplied by publisher]
Source: American Journal of Respiratory and Critical Care Medicine - Category: Respiratory Medicine Authors: Tags: Am J Respir Crit Care Med Source Type: research

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Authors: Pye A, Turner AM Abstract Introduction Alpha-1 antitrypsin deficiency (AATD) is most often associated with chronic lung disease, early onset emphysema and liver disease. The standard of care in lung disease due to AATD is alpha-1 antitrypsin augmentation but there are several new and emerging treatment options under investigation for both lung and liver manifestations. Areas covered We review therapeutic approaches to lung and liver disease in alpha-1 antitrypsin deficiency (AATD) and the agents in clinical development according to their mode of action. The focus is on products in clinical trials, but data...
Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
Conclusion: AAT augments macrophage control of M. intracellulare infection through enhancing phagosome-lysosome fusion and autophagy.
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
AbstractAlpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but c...
Source: Drugs and Aging - Category: Geriatrics Source Type: research
Alpha-1 antitrypsin deficiency (AATD) accounts for 5% of lung transplants performed worldwide. Ireland has a high frequency of 1 in 25 for the Z allele and 1 in 10 for the S allele [1]. These variants are associated with decreased production of alpha-1 antitrypsin (AAT), which predisposes to unprotected proteolytic activity of neutrophil elastase (NE) and proteinase 3 (PR3), linked to an increased risk of emphysema and hepatic disease. Associated inflammatory conditions such as vasculitis, panniculitis and inflammatory bowel disease are also suspected to be caused by uncontrolled neutrophil proteinase activity [2–4]....
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Original Articles: Research letters Source Type: research
Abstract Alpha-1 antitrypsin (AAT) deficiency is the leading genetic cause of emphysema; however, until recently, no genuine animal models of AAT deficiency existed hampering the development of new therapies. This shortcoming is now addressed by both AAT-null and antisense oligonucleotide mouse models. The goal of this study was to more fully characterize the antisense oligonucleotide model. Both liver AAT mRNA and serum AAT levels were lower in anti-AAT vs. control oligonucleotide treated mice after 6, 12, and 24-weeks. Six and twelve weeks of anti-AAT oligonucleotide therapy induced emphysema that was worse in f...
Source: Am J Physiol Lung Ce... - Category: Respiratory Medicine Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research
α1-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. ERdj3 is an ER luminal DnaJ homologue, which, along with calreticulin, directly interacts with misfolded ZAAT. We hypothesize that depletion of each of these chaperones will change the fate of ZAAT polymers. Our...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Cell Biology Source Type: research
Conclusion: Serum concentration and alleleic conformation of SFTPD has a significantly high predictive value for COPD and AECOPD. Thus, these can be tested further and could be applied as a predictive or prognostic marker. Introduction Chronic Obstructive Pulmonary Disease (COPD) affects lungs and exhibits irreversible airflow conditions that leads to improper respiratory function (Carolan et al., 2014). COPD is a global disease burden which accounts for ~3 million deaths annually (Zemans et al., 2017) and is responsible for the increase in worldwide mortality and morbidity (Dickens et al., 2011). Chronic Obstructi...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 15 April 2019Source: The Lancet Respiratory MedicineAuthor(s): Yohan Bossé, Maxime Lamontagne, Nathalie Gaudreault, Christine Racine, Marie-Hélène Levesque, Benjamin M Smith, Dominique Auger, Alisson Clemenceau, Marie-Ève Paré, Louis Laviolette, Victor Tremblay, Bruno Maranda, Mathieu C Morissette, François MaltaisSummaryBackgroundInherited mutations in SERPINA1 coding for the alpha-1 antitrypsin (A1AT) protein is the only well established cause of hereditary emphysema. We aimed to identify the genetic ecause of early-onset emphysema in a five-gen...
Source: The Lancet Respiratory Medicine - Category: Respiratory Medicine Source Type: research
Authors: Hersh CP Abstract INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, which presents the opportunity for precision therapy based on genetics or other biomarkers. Areas covered: Alpha-1 antitrypsin deficiency, a genetic form of emphysema, provides an example of this precision approach to diagnosis and therapy. To date, research in COPD pharmacogenomics has been limited by small sample sizes, lack of accessible target tissue, failure to consider COPD subtypes, and different outcomes relevant for various medications. There have been several published genome-wide associatio...
Source: Expert Review of Respiratory Medicine - Category: Respiratory Medicine Tags: Expert Rev Respir Med Source Type: research
Abstract Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Fortunately, over the past decade, the proliferation of genome-wide association studies (GWAS), the accessibility of whole genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in our understanding of genetic variant...
Source: American Journal of Respiratory and Critical Care Medicine - Category: Respiratory Medicine Authors: Tags: Am J Respir Crit Care Med Source Type: research
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