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Alpha 1 Antitrypsin

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Noel G. Mcelvaney – One of the best experts on this subject based on the ideXlab platform.

  • Alpha 1 Antitrypsin to treat lung disease in Alpha 1 Antitrypsin deficiency: recent developments and clinical implications.
    International journal of chronic obstructive pulmonary disease, 2018
    Co-Authors: Kenneth R. Chapman, Joanna Chorostowska-wynimko, A Rembert Koczulla, Ilaria Ferrarotti, Noel G. Mcelvaney

    Alpha 1 Antitrypsin deficiency is a hereditary condition characterized by low Alpha 1 proteinase inhibitor (also known as Alpha 1 Antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of Alpha 1 Antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to Alpha 1 Antitrypsin deficiency.

  • The Role of Neutrophils in Alpha1 Antitrypsin Deficiency.
    Annals of the American Thoracic Society, 2016
    Co-Authors: Cormac Mccarthy, Emer P. Reeves, Noel G. Mcelvaney

    Alpha1 Antitrypsin deficiency (AATD) is characterized by low levels of circulating Alpha1 Antitrypsin and an increased risk for emphysema, liver disease, and panniculitis. The reduced levels of Alpha1 Antitrypsin in AATD predispose the lung to unopposed proteolytic activity, predominantly from neutrophil-derived proteases, chiefly neutrophil elastase. This leads to emphysema. The mechanisms subtending the liver disease are less well understood, but are probably due to a “gain-of function” inflammatory process in the liver, stoked by intracellular retention of aberrantly folded Alpha1 Antitrypsin. The panniculitis associated with AATD is most likely due to unopposed proteolytic activity in the skin. Although AATD has been traditionally viewed as a condition arising from a protease-antiprotease imbalance in the lung, it is increasingly recognized that AATD is an inflammatory disorder, both in the lung and in the extrapulmonary manifestations associated with the condition. This inflammation is predominantly neutrophil driven, and there are several Alpha1 Antitrypsin-related mechanisms involved in potentiating this neutrophilic response. The rationale for AAT augmentation therapy in AATD is classically based on restoring the antiprotease balance in the lung, but its beneficial effects may also be exerted systemically, further exposing the pathogenesis of AATD-related disease and indicating a potential usage for Alpha1 Antitrypsin in other inflammatory conditions.

P. P. Reddy – One of the best experts on this subject based on the ideXlab platform.

  • Serum Alpha1Antitrypsin in smokers and non-smokers
    Indian Journal of Clinical Biochemistry, 1996
    Co-Authors: G. L. Somayajulu, Rao D. Raja, P. P. Reddy

    Serum Alpha1Antitrypsin assay was carried out in 21 smokers (mean age 44±8 yrs) and in 25 nonsmokers (mean age 44±7 yrs). The levels of serum Alpha1Antitrypsin expressed in umol/mt/ml were 2.97±0.85 for smokers and 3.08±0.37 for non-smokers and analysis of variance revealed no significant difference between these two groups. However in five smokers reduced levels (

Helle Krogh Johansen – One of the best experts on this subject based on the ideXlab platform.

  • intravenous Alpha 1 Antitrypsin augmentation therapy for treating patients with Alpha 1 Antitrypsin deficiency and lung disease
    Cochrane Database of Systematic Reviews, 2016
    Co-Authors: Peter C Gotzsche, Helle Krogh Johansen

    Background Alpha1 Antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain Alpha1 Antitrypsin, but it is uncertain what their clinical effect is. Objectives To review the benefits and harms of augmentation therapy with intravenous Alpha1 Antitrypsin in patients with Alpha1 Antitrypsin deficiency and lung disease. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and to 25 March 2016. Selection criteria We included randomised trials of augmentation therapy with Alpha1 Antitrypsin compared with placebo or no treatment. Data collection and analysis The two review authors independently selected trials, extracted outcome data and assessed the risk of bias. Main results We included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk of developing COPD. Only one trial reported mortality data (one person of 93 died in the treatment group and three of 87 died in the placebo group). There was no information on harms in the oldest trial. Another trial reported serious adverse events in 10 participants in the treatment group and 18 participants in the placebo group. In the most recent trial, serious adverse events occurred in 28 participants in each group. None of the trials reported mean number of lung infections or hospital admissions. In the two trials that reported exacerbations, there were more exacerbations in the treatment group than in the placebo group, but the results of both trials included the possibility of no difference. Quality of life was similar in the two groups. Forced expiratory volume in one second (FEV1) deteriorated more in participants in the treatment group than in the placebo group but the confidence interval (CI) included no difference (standardised mean difference -0.19, 95% CI -0.42 to 0.05; P = 0.12). For carbon monoxide diffusion, the difference was -0.11 mmol/minute/kPa (95% CI -0.35 to 0.12; P = 0.34). Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group (mean difference (MD) 0.86 g/L, 95% CI 0.31 to 1.42; P = 0.002). Several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest. Authors’ conclusions This review update added one new study and 143 new participants, but the conclusions remain unchanged. Due to sparse data, we could not arrive at a conclusion about the impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life, and there was uncertainty about possible harms. Therefore, it is our opinion that augmentation therapy with Alpha1 Antitrypsin cannot be recommended.

Hans-peter Fischer – One of the best experts on this subject based on the ideXlab platform.

  • Liver carcinoma in PiZ Alpha1Antitrypsin deficiency.
    The American journal of surgical pathology, 1998
    Co-Authors: Hui Zhou, Hans-peter Fischer

    One hundred sixty-four consecutive cases of primary liver carcinoma were evaluated for tumor type, (i.e., hepatocellular carcinoma [HCC], cholangiocarcinoma [CC], and combined hepatocholangiocarcinoma [CHCC]), and for signs of Alpha1Antitrypsin deficiency (AATD) in the surrounding liver tissue. Hepatocellular globular Alpha1Antitrypsin deposits, as detected by a monoclonal antibody to the mutant PiZ Alpha1Antitrypsin (AAT), were seen in 13 cases (7.9%). With regard to tumor type, 4 of 111 HCC cases (3.5%), but 4 of 37 CC cases (10.5%), and even 5 of 16 CHCC cases (30%) were positive for this Antitrypsin variant. In all but 1 of 13 cases of Alpha1Antitrypsin deficiency, the carcinoma developed in noncirrhotic liver tissue of elderly people (mean age, 62.9 years). In three patients, a heterozygous state of ATT (PiMZ) could be revealed using isoelectric focusing or direct genetic analysis. We conclude from our findings that CHCC and CC especially might be associated with PiZ Alpha1Antitrypsin deficiency. Primary liver carcinoma might develop even in a heterozygote state of PiZ Alpha1Antitrypsin deficiency without concurrent liver disease. Furthermore, liver cirrhosis is not a precondition for these tumors.

Christian Mueller – One of the best experts on this subject based on the ideXlab platform.

  • 5 year expression and neutrophil defect repair after gene therapy in Alpha 1 Antitrypsin deficiency
    Molecular Therapy, 2017
    Co-Authors: Christian Mueller, Emer P. Reeves, Gwladys Gernoux, Alisha M Gruntman, Florie Borel, Roberto Calcedo, Farshid N Rouhani, Anthony T Yachnis, Margaret Humphries

    Alpha1 Antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type Alpha1 Antitrypsin concentrations at 2.5%–3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 Alpha1 Antitrypsin vector in Alpha1 Antitrypsin deficient patients. We analyzed blood and muscle for Alpha1 Antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in Alpha1 Antitrypsin deficient patients. Here, we report sustained expression at 2.0%–2.5% of the target level from years 1–5 in these same patients without any additional recombinant adeno-associated virus serotype-1 Alpha1 Antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based Alpha1 Antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated.

  • The promise of gene therapy for the treatment of Alpha1 Antitrypsin deficiency.
    Pharmacogenomics, 2007
    Co-Authors: Pedro E. Cruz, Christian Mueller, Terence R. Flotte

    In the last 13 years, three gene therapy trials for the treatment of Alpha1 Antitrypsin deficiency have been conducted. The first trial delivered plasmid encoding the Alpha1 Antitrypsin cDNA to the nasal epithelium using cationic liposomes. The last two trials delivered recombinant adeno-associated vectors encoding the Alpha1 Antitrypsin cDNA by intramuscular injection. In this review, the progress of ongoing clinical trials and new gene therapy technologies is discussed.