Augmentation therapy for emphysema due to alpha-1-antitrypsin defiency

Servei de Pneumologia. Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain.
Therapeutic Advances in Respiratory Disease (Impact Factor: 1.95). 03/2008; 2(1):13-21. DOI: 10.1177/1753465807088159
Source: PubMed


Alpha-1 antitrypsin deficiency (AAT) is a hereditary recessive autosomal disease caused by mutations in the AAT gene. This disease is characterized by abnormally low AAT concentrations in plasma, which, in its homozygote form, carries a high risk for the development of early pulmonary emphysema and liver damage. Since the end of the 1980s augmentation therapy with AAT from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has been demonstrated to be safe and weekly infusions of AAT have resulted in plasma AAT concentrations above those considered protective for the lungs. However, life-long weekly infusions are not well accepted by patients, therefore pharmacokinetic studies have been performed to try to individualize the therapeutic regimen in order to obtain adequate trough serum AAT levels with prolonged intervals of administration. Therapeutic regimens administered every two weeks appear to be safe and result in adequate trough serum concentrations, but less-frequent administrations result in trough levels below the target. Alpha-1-antitrypsin deficiency is largely unrecognized and underdiagnosed. The foundation of national and international registries is a valid strategy to increase awareness about the disease and collect information about the natural history of this deficiency. Furthermore, the identification of a large number of patients will allow the development of new clinical trials aimed at finding better treatments for this infrequent condition.

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Available from: Marc Miravitlles, Jul 26, 2014
    • "Thus, low serum levels of circulating functional serine protease inhibitor primarily manifest as pulmonary emphysema or liver cirrhosis [42]. Augmentation therapy using intravenous infusions of human plasma-derived A1AT is still the only approved specific therapy for A1AT deficiency [43]. Multiple efforts have been made in recombinant A1AT production, but absent or altered glycosylation were major challenges [44]. "
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    ABSTRACT: Glycosylation is the most complex posttranslational modification. Thus, it contributes to versatile chemical compositions of proteins, leading to high amounts of protein species. The structural heterogeneity of glycoproteins was also described by the definition of glycoforms. We therefore introduced a new term called "glycoprotein species" to join the two concepts from different fields of biology. In this study, we further determined the theoretical numbers of glycoprotein species of two recombinant glycoproteins - a therapeutical antibody and the human protease inhibitor alpha-1-antitrypsin (A1AT) - based on structural analysis of their N-glycans. Moreover, we showed that variations in the used cell lines and their cultivation conditions strongly influence the number of glycoprotein species in case of recombinant A1AT production. Protein glycosylation is a major source for the huge amount of protein species. This study extends the sight of protein species by the following contributions: 1) The new term "glycoprotein species" was defined to introduce the concept of glycoforms into the field. 2) An estimation of the number of potential glycoprotein species of two particular glycoproteins was given. 3) The influence of production conditions for recombinant glycoproteins on glycoprotein species generation was displayed. Copyright © 2015. Published by Elsevier B.V.
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    • "The only specific treatment for patients with this disease is weekly intravenous infusion of human α1-AT obtained from blood donors [Tonelli and Brandly, 2010]. The indication for treatment includes identification of the deficient PI*ZZ or null genotypes [Tirado-Conde et al. 2008]. "
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    ABSTRACT: Alpha-1-antitrypsin (α1-AT) deficiency is mainly evaluated in the diagnostic process of chronic obstructive pulmonary disease (COPD). Around 95% of individuals with severe α1-AT deficiency carry the PI*ZZ genotype. Little is known about the epidemiology of the remaining deficient α1-AT variants, which are called 'rare' due to their low prevalence. The retrospective revision of 3511 α1-AT deficiency determinations performed in Barcelona from 1998 to 2010 detected 1.6% of cases with rare α1-AT alleles, a rate similar to those reported in other European studies. Among these variants, PI*I and PI*Mmalton represented 54% of cases. Hence, the so-called 'rare' α1-AT alleles may not be rare as has been assumed. It would be of interest to implement simple allele-specific molecular biology methods to study the most prevalent rare variants in each region. Augmentation therapy is recommended in patients with emphysema and PI*ZZ genotype, but there is little evidence regarding the implications of rare variants on therapy.
    Full-text · Article · Jan 2012 · Therapeutic Advances in Respiratory Disease
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    • "Intravenous administration of a pasteurized pooled human plasma AAT product (Prolastin; Bayer Corporation) is used to increase AAT levels in deficient individuals (4). This approach of therapy is practical and feasible (5, 6). However, there are two major obstacles; namely source limitation and risk for emerging viruses (7). "
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    ABSTRACT: Human alpha 1-antitrypsin (AAT) cDNA was obtained from HepG2 cell lines. After PCR and construction of expression vector pPICZα-AAT, human AAT was expressed in the yeast Pichia pastoris (P.pastoris) in a secretary manner and under the control of inducible alcohol oxidase 1 (AOX1) promoter. The amount of AAT protein in medium was measured as 60 mg/l 72 hr after induction with methanol. Results indicated the presence of protease inhibitory function of the protein against elastase. Purification was done using His-tag affinity chromatography. Due to the different patterns of glycosylation in yeast and human, the recombinant AAT showed different SDS-PAGE patterns compared to that of serum-derived AAT while pI shifted from 4.9 in native AAT compared to 5.2 in recombinant AAT constructed in this study.
    Full-text · Article · Jul 2011
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