scholarly journals Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches

2021 ◽  
Vol 22 (3) ◽  
pp. 1065
Author(s):  
Simona Viglio ◽  
Elisabeth G. Bak ◽  
Iris G. M. Schouten ◽  
Paolo Iadarola ◽  
Jan Stolk
Keyword(s):  
Serine Proteases ◽  
Lung Parenchyma ◽  
New Drugs ◽  
Chronic Obstructive ◽  
Augmentation Therapy ◽  
Lung Function Decline ◽  
Obstructive Pulmonary Disease ◽  
Antitrypsin Deficiency ◽  
Novel Biomarkers ◽  
Alpha1 Antitrypsin

As a known genetic cause of chronic obstructive pulmonary disease (COPD), alpha1-antitrypsin deficiency (AATD) can cause severe respiratory problems at a relatively young age. These problems are caused by decreased or absent levels of alpha1-antitrypsin (AAT), an antiprotease which is primarily functional in the respiratory system. If the levels of AAT fall below the protective threshold of 11 µM, the neutrophil-derived serine proteases neutrophil elastase (NE) and proteinase 3 (PR3), which are targets of AAT, are not sufficiently inhibited, resulting in excessive degradation of the lung parenchyma, increased inflammation, and increased susceptibility to infections. Because other therapies are still in the early phases of development, the only therapy currently available for AATD is AAT augmentation therapy. The controversy surrounding AAT augmentation therapy concerns its efficiency, as protection of lung function decline is not demonstrated, despite the treatment’s proven significant effect on lung density change in the long term. In this review article, novel biomarkers of NE and PR3 activity and their use to assess the efficacy of AAT augmentation therapy are discussed. Furthermore, a series of seven synthetic NE and PR3 inhibitors that can be used to evaluate the specificity of the novel biomarkers, and with potential as new drugs, are discussed.

scholarly journals Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know

2021 ◽  
Vol 12_suppl ◽  
pp. 204062232110101
Author(s):  
Igor Barjaktarevic ◽  
Michael Campos
Keyword(s):  
Lung Disease ◽  
Treatment Guidelines ◽  
Management Program ◽  
Lifestyle Changes ◽  
Chronic Obstructive ◽  
Augmentation Therapy ◽  
Lung Function Decline ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

scholarly journals The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency

2021 ◽  
Vol 12_suppl ◽  
pp. 204062232199569
Author(s):  
Vickram Tejwani ◽  
James K. Stoller
Keyword(s):  
Case Series ◽  
Antineutrophil Cytoplasmic Antibody ◽  
The United States ◽  
Chronic Obstructive ◽  
Augmentation Therapy ◽  
Obstructive Pulmonary Disease ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Dominant Condition

Alpha-1 antitrypsin (AAT) deficiency (AATD) is an autosomal co-dominant condition that predisposes to the development of lung disease, primarily emphysema. Emphysema results from the breakdown of lung matrix elastin by proteases, including neutrophil elastase, a protease normally inhibited by AAT. AATD also predisposes to liver (cirrhosis) and skin (panniculitis) disease, and to vasculitis. The prevalence of AATD is estimated to be approximately 1 in 3,500 individuals in the United States. However, lack of awareness of AATD among some physicians, misperceptions regarding the absence of effective therapy, and the close overlap in symptoms with asthma and non-AATD chronic obstructive pulmonary disease are thought to contribute to under-recognition of the disease. In patients with AATD, treatment with intravenous AAT augmentation therapy is the only currently available treatment known to slow the progression of emphysema. Moreover, smoking cessation and other lifestyle interventions also help improve outcomes. Early diagnosis and intervention are of key importance due to the irreversible nature of the resultant emphysema. Liver disease is the second leading cause of death among patients with AATD and a minority of patients present with panniculitis or antineutrophil cytoplasmic antibody-associated vasculitis, thought to be directly related to AATD. Though no randomized trial has assessed the effectiveness of augmentation therapy for AATD-associated panniculitis, clinical experience and case series suggest there is a benefit. Other diseases putatively linked to AATD include aneurysmal disease and multiple neurological conditions, although these associations remain speculative in nature.

scholarly journals Case-finding for alpha1-antitrypsin deficiency in Kazakh patients with COPD

2017 ◽  
Vol 12 ◽  
Author(s):  
Ilaria Ferrarotti ◽  
Ardak Zhumagaliyeva ◽  
Stefania Ottaviani ◽  
Timm Greulich ◽  
Marina Gorrini ◽  
...  
Keyword(s):  
Large Population ◽  
General Concept ◽  
Dried Blood Spot ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Care Givers ◽  
Kazakh Population ◽  
Antitrypsin Deficiency ◽  
Alpha1 Antitrypsin ◽  
Blood Spot

Background: Alpha-1-antitrypsin deficiency (AATD) is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to screen for AATD in Kazakh patients with COPD using dried blood spot specimens. Methods: The alpha1-antitrypsin (AAT) concentration was determined by nephelometry, PCR was used to detect PiS and PiZ alleles; and isoelectric focusing was used to confirm questionable genotype results and detect rare AAT variants. Results: To this aim, 187 Kazakh subjects with COPD were recruited. Blood samples were collected as dried blood spot. Genotyping of 187 samples revealed 3 (1.6%) PI*MZ and 1 (0.53%) PI*MS, Phenotyping identified also two sample (1.1%) with phenotype PiMI. Allelic frequencies of pathological mutations Z, S and I resulted 0.8%, 0.3%, 0.5%, respectively, in COPD Kazakh population. Conclusions: This study proved that AATD is present in the Kazakh population. These results support the general concept of targeted screening for AAT deficiency in countries like Kazakhstan, with a large population of COPD patients and low awareness among care-givers about this genetic condition.

scholarly journals The Emerging Role of Proteases in Alpha-1 Antitrypsin Deficiency and Beyond

2021 ◽  
pp. 00494-2021
Author(s):  
Aishath Fazleen ◽  
Tom Wilkinson
Keyword(s):  
Serine Proteases ◽  
Treatment Options ◽  
Disease Process ◽  
Cathepsin G ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Lung Diseases ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Alpha-1 Antitrypsin Deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis, or a combination of phenotypes) has not been proposed or studied. Of the 3 Neutrophil Serine Proteases (NSPs), Neutrophil Elastase (NE) was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 (PR3) has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G (CG), however, has not been extensively evaluated in this area. Matrix metalloproteinases (MMPs) have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Due to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including chronic obstructive pulmonary disease (COPD) and bronchiectasis have been made. We consider a new framework of understanding defined by protease driven endotypes of disease which may lead to new opportunities for precision medicine.

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