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      Alpha-1 antitrypsin deficiency: outstanding questions and future directions

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          Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved.


          In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research.


          1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed.


          2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.

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          Most cited references 125

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          Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.

          Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what we believe to be a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (alpha1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded alpha1-antitrypsin in the endoplasmic reticulum, deficient LDL receptor-mediated cholesterol uptake, and elevated lipid and glycogen accumulation. Therefore, we report a simple and effective platform for hepatocyte generation from patient-specific human iPS cells. These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells.
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            An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.

            In the classical form of alpha1-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant alpha1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease. These results provide a basis for testing CBZ, which has an extensive clinical safety profile, in patients with AT deficiency and also provide a proof of principle for therapeutic use of autophagy enhancers.
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              Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

              The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.

                Author and article information

                +34676515598 , Francisco.Dasi@uv.es
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                11 July 2018
                11 July 2018
                : 13
                [1 ]Pulmonary Department, Hospital Álvaro Cunqueiro EOXI, Vigo, Spain
                [2 ]NeumoVigo I+i Research Group, IIS Galicia Sur, Vigo, Spain
                [3 ]Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Sevilla, Spain
                [4 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER de Enfermedades Respiratorias (CIBERES), ; Madrid, Spain
                [5 ]ISNI 0000 0001 0675 8654, GRID grid.411083.f, Pneumology Department, , Hospital Universitari Vall d’Hebron, ; Barcelona, Spain
                [6 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Molecular Genetics Unit, Instituto de Investigación de Enfermedades Raras (IIER), , Instituto de Salud Carlos III (ISCIII), ; Madrid, Spain
                [7 ]Fundación Investigación Hospital Clínico Valencia, Instituto de Investigación Sanitaria INCLIVA, c/Menéndez y Pelayo, 4, 46010 Valencia, Spain
                [8 ]ISNI 0000 0001 2173 938X, GRID grid.5338.d, School of Medicine, Department of Paediatrics, Obstetrics and Gynaecology, , University of Valencia, ; Valencia, Spain
                [9 ]Pneumology Department, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
                [10 ]ISNI 0000 0001 2173 938X, GRID grid.5338.d, School of Medicine, Department of Physiology, Research group on Rare Respiratory Diseases (ERR), , University of Valencia, ; Valencia, Spain
                [11 ]GRID grid.459499.c, Pneumology Department, , Hospital Universitario San Cecilio, ; Granada, Spain
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PI17/01250
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007509, Sociedad Española de Neumología y Cirugía Torácica;
                Award ID: 201/2013
                Award Recipient :
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                © The Author(s) 2018


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