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Background: Currently, there is conflicting information and guidance on the effective management of Alpha 1 Antitrypsin Deficiency (AATD). Establishing a consensus of assessment and disease management specific to AATD is important for achieving a standardized treatment pathway and for improving patient outcomes. Here, we aim to utilize the Delphi method to establish a European consensus for the assessment and management of patients with severe AATD., Methods: Two rounds of a Delphi survey were completed online by members of the European Alpha-1 Research Collaboration (EARCO). Respondents were asked to indicate their agreement with proposed statements for patients with no respiratory symptoms, stable respiratory disease, and worsening respiratory disease using a Likert scale of 1-7. Levels of agreement between respondents were calculated using a weighted average., Results: Round 1 of the Delphi survey was sent to 103 members of EARCO and 38/103 (36.9%) pulmonologists from across 15 countries completed all 109 questions. Round 2 was sent to all who completed Round 1 and 36/38 (94.7%) completed all 79 questions. Responses regarding spirometry, body plethysmography, high-resolution computed tomography, and the initiation of augmentation therapy showed little variability among physicians, but there was discordance among other aspects, such as the use of low-dose computed tomography in both a research setting and routine clinical care., Conclusions: These results provide expert opinions for the assessment and monitoring of patients with severe AATD, which could be used to provide updated recommendations and standardized treatment pathways for patients across Europe., (© 2024. The Author(s).)

Human induced pluripotent stem cell (iPSC) and CRISPR-Cas9 gene-editing technologies have become powerful tools in disease modeling and treatment. By harnessing recent biotechnological advancements, this review aims to equip researchers and clinicians with a comprehensive and updated understanding of the evolving treatment landscape for metabolic and genetic disorders, highlighting how iPSCs provide a unique platform for detailed pathological modeling and pharmacological testing, driving forward precision medicine and drug discovery. Concurrently, CRISPR-Cas9 offers unprecedented precision in gene correction, presenting potential curative therapies that move beyond symptomatic treatment. Therefore, this review examines the transformative role of iPSC technology and CRISPR-Cas9 gene editing in addressing metabolic and genetic disorders such as alpha-1 antitrypsin deficiency (A1AD) and glycogen storage disease (GSD), which significantly impact liver and pulmonary health and pose substantial challenges in clinical management. In addition, this review discusses significant achievements alongside persistent challenges such as technical limitations, ethical concerns, and regulatory hurdles. Future directions, including innovations in gene-editing accuracy and therapeutic delivery systems, are emphasized for next-generation therapies that leverage the full potential of iPSC and CRISPR-Cas9 technologies.

Alpha 1‑antitrypsin (AAT) deficiency represents a complex genetic disorder and necessitates an interdisciplinary approach in the clinical practice. This article provides an overview of the epidemiology, genetics, symptoms, diagnostics and treatment of AAT deficiency. Knowledge and an in-depth understanding of AAT deficiency are indispensable to improve the early recognition of AAT, to optimize the quality of life of those affected and to enable targeted treatment interventions., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition caused by decreased plasma and tissue levels of alpha-1 antitrypsin (AAT) that can lead to serious lung and liver disease in children and adults. AATD patients face challenges such as under diagnosis, clinical variability, and limited treatment options for liver disease. Early detection and biomarkers for predicting outcomes are needed to improve patient outcome. Currently, the only approved pharmacological therapy is augmentation therapy, which can delay the progression of emphysema. However, alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated. This review aims to summarize and update current knowledge on AATD, identify areas of controversy, and formulate questions for further research., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Five distinct gene therapy approaches have been developed for treating AATD. These approaches include knockout of the mutant (PiZ) allele by introduction of double-strand breaks (DSBs) and subsequent creation of insertions and deletions (indels) by DSB repair, homology-directed repair (HDR) targeted to the mutation site, base editing, prime editing, and alternatively targeted knock-in techniques. Each approach will be discussed and a brief summary of a standard CRISPR-Cas9 targeting method will be presented., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite initiatives to improve awareness and treatment of alpha-1 antitrypsin deficiency (AATD), country-level processes for AATD management remain unclear., Objectives: We conducted a pan-European physician survey to clarify the pathways for AATD care., Method: Professionals involved in AATD diagnosis and/or management completed a web-based survey on the detection, evaluation, monitoring and treatment of AATD and the utilisation of European reference network centres for rare lung diseases (ERN-LUNG)., Results: Surveys were completed by 166 physicians from 18 European countries. Overall, 25 % of respondents were unaware of local specific AATD testing guidelines, and most (72 %) had referred <10 patients to a specialist. However, there was general agreement regarding reasons for referral and the types of patient referred. Approaches to AATD testing are heterogenous, with significant between-country differences in the sample testing and collection methods used. Alpha-1 antitrypsin therapy is most frequently monitored using spirometry (98 %), gas transfer (79 %) or symptoms (82 %). Overall, 28 % of respondents were unfamiliar with ERN-LUNG centres, with Portugal and Spain reporting the lowest familiarity, and use of these centres for patient evaluation varied widely. However, engagement with ERN-LUNG centres was widely agreed to be useful when it did occur (especially in Italy and Poland). Little cross-border use of ERN-LUNG centres for patient testing/evaluation was reported., Conclusions: European care pathways for AATD are largely uniform, but with notable heterogeneity in testing approaches and a need for education and standardisation. Familiarity with and use of ERN-LUNG AATD services is variable, and increased awareness of these services is warranted., Competing Interests: Declaration of competing interest The physician survey and development of this manuscript was funded by CSL Behring. Medical writing assistance was provided by Meridian HealthComms Ltd, UK, and statistical support was provided by Statsconsultancy Ltd., both funded by CSL Behring. Maria Sucena reports speaker or consulting fees from Bial, Boehringer Ingelheim, CSL Behring, Grifols, Novartis, and personal fees from Bial, Boehringer Ingelheim, CSL Behring, DarSaúde, Gasoxmed, Grifols, Linde, Menarini, Novartis and VitalAire. Joanna Chorostowska-Wynimko reports research grants, speaker and consulting fees from Grifols, CSL Behring, CelonPharma, Pfizer, AstraZeneca, Boehringer-Ingelheim, speaker and consulting fees from Mereo Biopharma, MSD, BMS, GSK, Novartis, Roche, Chiesi, Amgen, Takeda. A Rembert Kockzulla reports no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alpha1-antitrypsin deficiency (AATD) is a rare autosomal recessive disease associated with the homozygous Z variant of the SERPINA1 gene. Clinical expression of AATD, reported 60 years ago associate a severe deficiency, pulmonary emphysema and/or liver fibrosis. Pulmonary emphysema is due to the severe alpha1-antitrypsin deficiency of the ZZ homozygous status and is favored by smoking. Liver fibrosis is due to the ZZ homozygous status and is favored by obesity and excessive chronic alcohol intake, with a risk of liver cancer. Diagnosis is based on serum level and either isoelectric focusing determination of the biochemical phenotype or PCR detection of some variants. SERPINA1 gene sequencing is necessary in case of discrepancies between the results of these tests. No treatment is available for the liver disease in AATD. Although no specific trial has been performed, COPD in AATD should be treated as per COPD recommendations. Based on a randomized clinical trial, augmentation therapy is indicated in non-smoking adults less than 70 years of age with emphysema at chest CT, confirmed homozygous AATD, and FEV1 between 35% and 70% of predicted. In contrast Z heterozygosis (MZ or SZ) brings a risk of lung or liver disease only in association with further risk factors. Early detection, in all patients with COPD and chronic liver disease, is critical for the correct information of Z variant carriers. News ways of correcting the liver production of alpha1-antitrypsin will modify the care of AATD patients., Competing Interests: Declaration of Competing Interest The authors have not supplied their declaration of competing interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1 , the AAT gene that impairs the production or secretion of this hepatocellular protein and leads to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2 to 10% of carriers as neonatal cholestasis and 20 to 35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies., Competing Interests: M.R. received advisory board fees and lecture fees from Takeda, advisory board fees from Grifols, lecture fees from CSL Behring. P.S. received grant support and lecture fees from Grifols and CSL Behring; grant support and advisory board fees from Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals; grant support from Vertex Pharmaceuticals; advisory board fees from GSK, Intellia Pharmaceuticals, Novo Nordisk, Takeda, and Ono Pharmaceuticals; and is supported by the Deutsche Forschungsgemeinschaft (DFG) grants SFB 1382 (ID 403224013) and STR 1095/6–1., (Thieme. All rights reserved.)

Introduction: Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin ( SERPINA1 ) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism., Areas Covered: This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases., Expert Opinion: Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder and a genetic risk factor for chronic obstructive pulmonary disease (COPD). Physical activity (PA) is important for the prevention and treatment of chronic disease. Little is known about PA in people with AATD. Therefore, we aimed to map the research undertaken to improve and/or measure PA, sedentary behaviour (SB) or exercise in people with AATD. Searches were conducted in CINAHL, Medline, EMBASE and clinical trial databases for studies published in 2021. Databases were searched for keywords (physical activity, AATD, exercise, sedentary behavior) as well as synonyms of these terms, which were connected using Boolean operators. The search yielded 360 records; 37 records were included for review. All included studies (n = 37) assessed exercise capacity; 22 studies reported the use of the six-minute walk test, the incremental shuttle walk test and cardiopulmonary exercise testing were reported in three studies each. Other objective measures of exercise capacity included a submaximal treadmill test, the Naughton protocol treadmill test, cycle ergometer maximal test, endurance shuttle walk test, constant cycle work rate test, a peak work rate test and the number of flights of stairs a participant was able to walk without stopping. A number of participant self-reported measures of exercise capacity were noted. Only one study aimed to analyze the effects of an intensive fitness intervention on daily PA. One further study reported on an exercise intervention and objectively measured PA at baseline. No studies measured SB. The assessment of PA and use of PA as an intervention in AATD is limited, and research into SB absent. Future research should measure PA and SB levels in people with AATD and explore interventions to enhance PA in this susceptible population., Competing Interests: Professor Noel G McElvaney reports grants from Grifols, Csl Behring; advisory board for vertex and inhibrx, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 O’Shea et al.)

Introduction: Altering the human genetic code has been explored since the early 1990s as a definitive answer for the treatment of monogenic and acquired diseases which do not respond to conventional therapies. In Alpha-1 antitrypsin deficiency (AATD) the proper synthesis and secretion of alpha-1 antitrypsin (AAT) protein is impaired, leading to its toxic hepatic accumulation along with its pulmonary insufficiency, which is associated with parenchymal proteolytic destruction. Because AATD is caused by mutations in a single gene whose correction alone would normalize the mutant phenotype, it has become a popular target for both augmentation gene therapy and gene editing. Although gene therapy products are already a reality for the treatment of some pathologies, such as inherited retinal dystrophy and spinal muscular atrophy, AATD-related pulmonary and, especially, liver diseases still lack effective therapeutic options., Areas Covered: Here, we review the course, challenges, and achievements of AATD gene therapy as well as update on new strategies being developed., Expert Opinion: Reaching safe and clinically effective expression of the AAT is currently the greatest challenge for AATD gene therapy. The improvement and emergence of technologies that use gene introduction, silencing and correction hold promise for the treatment of AATD.

Introduction: Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. In this review, we discuss the therapies presently available for the different manifestations of AATD and new therapies in the pipeline., Areas Covered: We review therapeutic options for the individual lung, liver and skin manifestations of AATD along with approaches which aim to treat all three. Along with this renewed interest in treating AATD come challenges. How is AAT best delivered to the lung? What is the desired level of AAT in the circulation and lungs which therapeutics should aim to provide? Will treating the liver disease increase the potential for lung disease? Are there treatments to target the underlying genetic defect with the potential to prevent all aspects of AATDrelated disease?, Expert Opinion: With a relatively small population able to participate in clinical studies, increased awareness and diagnosis of AATD is urgently needed. Better, more sensitive clinical parameters will assist in the generation of acceptable and robust evidence of therapeutic effect for current and emerging treatments.

α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early-onset panacinar emphysema. AAT, produced primarily in the liver, functions to protect the lung from neutrophil protease; with AAT deficiency, unimpeded neutrophil proteases destroy the lung parenchyma. AAT is susceptible to oxidative damage resulting in an inability to inhibit its target proteases, neutrophil elastase, and cathepsin G. The major sites of oxidative modification on the AAT molecule are methionine residues 351 and 358. We have previously demonstrated that an engineered variant of AAT that resists oxidation by modifying both protein surface methionines (M351V and M358L) provides antiprotease protection, despite oxidative stress. In mice, intravenous delivery of the modified AAT(AVL) variant by AAV serotype 8, AAV8hAAT(AVL), primarily to the liver resulted in long-term expression of an AAT that resists oxidative inactivation. In this study, we evaluated the safety of intravenous administration of AAV8hAAT(AVL) in a dose-escalating, blinded, placebo-controlled toxicology study in wild-type mice. The study assessed organ histology and clinical pathology findings of mice, intravenously administered AAV8hAAT(AVL) at three doses (5.0 × 10 11 , 5.0 × 10 12 , and 5.0 × 10 13 genome copies [gc]/kg), compared to control mice injected intravenously with phosphate-buffered saline. As previously demonstrated, administration of AAV8hAAT(AVL) resulted in dose-dependent expression of high, potentially therapeutic, levels of serum human AAT protein that persist for at least 6 months. Antibodies against the AAV8 capsid were elicited as expected, but there was no antibody detected against the AAT(AVL) protein generated by the AAV8hAAT(AVL) vector. There was no morbidity or mortality observed in the study. The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose. This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.

Alpha 1-antitrypsin deficiency is an inherited autosomal codominant disorder, which predisposes patients to lung and/or liver disease. Even though it is considered rare, it is one of the most frequent genetic disorders worldwide, albeit remaining underdiagnosed. Several organizations and societies, including the Portuguese Society of Pulmonology have been elaborating guidelines and recommendations for the diagnosis and management of alpha 1-antitrypsin deficiency. Nevertheless, some important matters are yet to be included in those, mainly due to lack of robust scientific evidence, and continue to represent a point of discussion. This article reviews some important scientific publications and expresses the perspectives of a group of Portuguese experts regarding the management of alpha 1-antitrypsin deficiency, namely in terms of the pre and neonatal diagnosis, the impact of the COVID-19 pandemic, the validity of replacement therapy in lung transplant-receiving, and finally, alternative strategies of alpha 1-antitrypsin deficiency treatment to improve the patients' quality of life.

Alpha-1 antitrypsin deficiency (DAAT) is a rare autosomal recessive genetic disorder caused by mutations in the Serpina1 gene. The role of alpha-1 antitrypsin (A1AT) is to maintain homeostasis in the acute phase of inflammation. DAAT manifests itself primarily in carriers of the Z allele, especially in the homozygous state, as emphysema and chronic liver disease. Although the diagnostic strategy is well defined and screening is fully reimbursed, DAAT is still largely underdiagnosed. In addition to simple lifestyle advice, which is essential once the diagnosis has been made, the specific treatment for severe deficiency and lung involvement is based on substitution with purified human A1AT, which slows the development of pulmonary emphysema., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Liver disease in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency occurs due to the accumulation of large quantities of AAT mutant Z protein polymers in the liver. The mutant Z protein folds improperly during biogenesis and is retained within the hepatocytes rather than appropriately secreted. These intracellular polymers trigger an injury cascade, which leads to liver injury. However, the clinical liver disease is highly variable and not all patients with this same homozygous ZZ genotype develop liver disease. Evidence suggests that genetic determinants of intracellular protein processing, among other unidentified genetic and environmental factors, likely play a role in liver disease susceptibility. Advancements made in development of new treatment strategies using siRNA technology, and other novel approaches, are promising, and multiple human liver disease trials are underway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Alpha1-antitrypsin deficiency (AATD) is a genetic-based risk condition, mainly affecting the lungs and liver. Despite its wide distribution, it is largely underdiagnosed, thus being considered a rare disease, and is consequently managed in ad-hoc reference centers. Unfortunately, an easy-to-use algorithm for managing such a complex disease is still lacking., Methods: An expert consensus meeting was conducted among experts in the management of AATD to build a comprehensive algorithm, including diagnosis, monitoring, AAT therapy, rehabilitation and lung transplantation, and liver disease, that could serve as a guide for physicians and treating centers. A panel of AATD specialists evaluated the results of their work., Results: Diagnosis is the most delicate phase, and awareness about this condition should be raised among GPs. A set of recommendations has been written about the most suitable follow-up visits. Augmentation therapy with AAT may be useful to reduce the progression of emphysema and lung function decline in selected patients. Exercise capacity may be improved by pulmonary rehabilitation and, in selected cases, by lung volume reduction or lung transplantation. Support therapies are needed for those who develop liver disease, and, in selected cases, liver transplantation may be considered. Patients should be carefully educated about their lifestyle, including smoking cessation, body weight control, and reduced alcohol intake., Conclusions: The proposed algorithm obtained the endorsement of the Italian Society of Pneumology (SIP). However, further studies and additional clinical data are required to confirm the validity of these recommendations.

Alpha-1 antitrypsin deficiency (AATD) is a rare autosomal codominant disease caused by mutations within the SERPINA1 gene. The most prevalent variant in patients is PiZ SERPINA1, containing a single G > A transition mutation. PiZ alpha-1 antitrypsin (AAT) is prone to misfolding, leading to the accumulation of toxic aggregates within hepatocytes. In addition, the abnormally low level of AAT secreted into circulation provides insufficient inhibition of neutrophil elastase within the lungs, eventually causing emphysema. Cytosine and adenine base editors enable the programmable conversion of C⋅G to T⋅A and A⋅T to G⋅C base pairs, respectively. In this study, two different base editing approaches were developed: use of a cytosine base editor to install a compensatory mutation (p.Met374Ile) and use of an adenine base editor to mediate the correction of the pathogenic PiZ mutation. After treatment with lipid nanoparticles formulated with base editing reagents, PiZ-transgenic mice exhibited durable editing of SERPINA1 in the liver, increased serum AAT, and improved liver histology. These results indicate that base editing has the potential to address both lung and liver disease in AATD., Competing Interests: Declaration of interests M.S.P., G.L., L.C., Y.A.S., D.L., S.S., A.S., D.C., B.J.C., B.Y., G.C., and F.M.G. are employees of and shareholders in Beam Therapeutics. This work was funded in part by Beam Therapeutics, which develops base editing therapeutics., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large-animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared with matched controls using custom-designed flexiVent modules to perform pulmonary function tests, quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, and reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.

Purpose of Review: In this review, we will discuss the current status and recent developments in precision medicine in chronic obstructive pulmonary disease (COPD) through the lens of treatable traits., Recent Findings: Although the term 'treatable traits' in the treatment of COPD is relatively recent, this concept has been used for many years if one considers interventions such as long-term oxygen therapy or alpha-1 antitrypsin replacement therapy. Recent advances have included expanding the definition of COPD to include a broader population of people with lower respiratory disease but not meeting the strict criteria for obstruction, advances in imaging to aid in the diagnosis and treatment of COPD, advances in understanding symptoms and exacerbations to define severity, using biomarkers to guide therapy and better understanding and addressing polymorbidity and frailty. In addition, there is a concerted effort to use these concepts to identify COPD patients earlier in the disease process wherein disease modification may be possible., Summary: Focusing on subsets of patients with COPD with certain characteristics should lead to better outcomes and fewer adverse effects from treatment., Video Abstract: http://links.lww.com/COPM/A30., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This is a report of a 45-year-old female with thoracic central venous obstruction (TCVO) and alpha-1 antitrypsin deficiency requiring an implanted port for infusions. The azygos vein was used for catheter access in the setting of an occluded right internal jugular vein, bilateral innominate, and superior vena cava. A literature review examines the etiology of TCVO and superior vena cava syndrome (SVC), as well as the potential benefits and complications for using the azygos vein in patients with TCVO requiring port or catheter venous access., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Alpha-1 antitrypsin deficiency occurs in individuals with deleterious genetic mutations on both chromosomes (maternal and paternal) in SERPINA1 , the gene encoding the alpha-1 antitrypsin protein. There has been substantial progress in understanding the genetic variation that underlies the heterogeneous penetrance of lung disease in alpha-1 antitrypsin deficiency., Areas Covered: This review will cover SERPINA1 gene structure and genetic variation, population genetics, genome-wide genetic modifiers of lung disease, alternative mechanisms of disease, and emerging therapeutics - including gene and cell therapy - related to alpha-1 antitrypsin deficiency-associated lung disease., Expert Opinion: There remains ample opportunity to employ precision medicine in the diagnosis, prognosis, and therapy of alpha-1 antitrypsin deficiency-associated lung disease. In particular, a genome-wide association study and subsequent polygenic risk score is an important first step in identifying genome-wide genetic modifiers contributing to the variability of lung disease in severe alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single-base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole-genome sequencing. These results reveal the feasibility and utility of base editing to correct the Z mutation in AATD patient cells., Competing Interests: Declaration of interests Support for this work was provided in the form of a research grant from Beam Therapeutics to A.A.W. M.S.P., L.E.Y., Y.A.-S., and F.G. are employed by Beam Therapeutics and contributed to data collection, data analysis, and manuscript preparation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that mainly affecting the liver and the lung. This creates difficulties to ensure that comprehensive care is administered to both organ systems. Past assessments of care delivered to patients with AATD demonstrated that improvements are needed. For that reason, we reassessed a population of patients with AATD in a large health care system to see if past findings affected present care. Methods: We performed electronic health record (EHR) reviews on all patients with documented AATD and confirmed the diagnosis by evidence of genotyping. We then selected the patients with the ZZ genotype to review comprehensive care. We further compared the findings in patients treated by different specialists (allergy immunology, gastroenterology, and pulmonary). The data were captured and assessed by using a secure web application for building and managing online surveys and data bases. REDCap. Results: We found a total of 329 patients with diagnostic codes for AATD, of these, 203 patients had a confirmed abnormal genotype. Confirmed genotypes were MZ (n = 69), ZZ (n = 48), MS (n = 22), SZ (n = 22). Further focus was applied to the care of the ZZ population secondary to a predisposition to potential severe lung and liver disease. The findings suggest that care can be improved no matter which specialist cares for the patient. Conclusion: Our study demonstrated that all three subspecialty groups had room for improvement in providing care to patients with AATD. Our study further demonstrated the need for recurrent quality-assurance programs that may be aided by care suggestions built into the EHR.

Inherited deficiency of the antiprotease alpha-1 antitrypsin (AAT) is associated with liver failure and early-onset emphysema. In mice, in vivo lentiviral transduction of alveolar macrophages (AMs) has been described to yield protective pulmonary AAT levels and ameliorate emphysema development. We here investigated the pulmonary transplantation of macrophages (PMT) transgenic for AAT as a potential therapy for AAT deficiency-associated lung pathology. Employing third-generation SIN-lentiviral vectors expressing the human AAT cDNA from the CAG or Cbx-EF1α promoter, we obtained high-level AAT secretion in a murine AM cell line as well as murine bone marrow-derived macrophages differentiated in vitro (AAT MΦ). Secreted AAT demonstrated a physiologic glycosylation pattern as well as elastase-inhibitory and anti-apoptotic properties. AAT MΦ preserved normal morphology, surface phenotype, and functionality. Furthermore, in vitro generated murine AAT MΦ successfully engrafted in AM-deficient Csf2rb -/- mice and converted into a CD11c + /Siglec-F + AM phenotype as detected in bronchoalveolar lavage fluid and homogenized lung tissue 2 months after PMT. Moreover, human AAT was detected in the lung epithelial lining fluid of transplanted animals. Efficient AAT expression and secretion were also demonstrated for human AAT MΦ, confirming the applicability of our vectors in human cells., (© 2021. The Author(s).)

In this work, we provide an up-to-date summary of the available molecular- and cell-related mechanisms by which alpha1-antitrypsin (AAT) protein could be of benefit in treating COVID-19 patients. As well, we demonstrate the current status in terms of the ongoing clinical trials using AAT in COVID-19 patients. Finally, we touch on the potential role gene therapy and stem cell-based gene therapy could have in such emerging and serious condition caused by the SARS-CoV-2 virus., (© 2021 John Wiley & Sons Ltd.)

Competing Interests: CY is a former postdoctoral fellow at the University Health Network. HZ declares no competing interests.

Introduction : Therapeutic oligonucleotides have emerged as a promising new class of drug that could silence undruggable targets; they can potentially treat metabolic liver diseases such as nonalcoholic fatty liver disease (NAFLD), hereditary hemochromatosis and alpha 1 antitrypsin deficiency. Areas covered : This article illuminates the mechanism of action of, and drug delivery approaches for therapeutic oligonucleotides such as antisense oligonucleotides (ASOs), short interfering RNAs (siRNAs), and MicroRNAs (miRs). We reveal why the liver is the ideal organ for therapeutic oligonucleotides, discuss its unique architecture, and shed light on those susceptible molecular targets that can be modulated. We also examine preclinical and clinical data on the utility of oligonucleotides in silencing the expression of genes responsible for metabolic liver diseases. Expert opinion : The liver has numerous susceptible molecular therapeutic targets; hence, metabolic liver diseases can be treated effectively by modulating these targets via novel therapeutic oligonucleotides. Undoubtedly, these exciting developments integrate well with precision medicine progress. Specific therapeutic oligonucleotides can be designed based on the exact underlying molecular mechanism of the disease. So, there is a justification for furthering the development of therapeutic oligonucleotides for metabolic liver diseases. Safety concerns such as immunogenicity and off-target effects will however require careful monitoring.

Alpha-1 antitrypsin deficiency is an autosomal codominant genetic disease characterized by low levels of alpha-1 antitrypsin in the blood. Clinically, in young patients, it mainly manifests as emphysema, acute/chronic liver injury and liver cancer. The treatment methods include symptomatic treatment and alpha -1 antitrypsin supplementation. However, the existing treatment cannot prevent the liver fibrosis progression. At present, more than ten cases of the disease have been reported in China, but the understanding of this disease is still indecisive. Moreover, there exists no biotherapy drug for this disorder. This article introduces the research progress of hepatocyte transplantation treatment for this disorder.

AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector-meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium-targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus- and adenoviral vector-mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation.

Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Cigarette smoke, pollution, and inflammatory cell-mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/L358; 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358; 8/AMM). 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL serum and ELF retained serine protease-inhibitory activity despite oxidant stress while 8/AMM function was abolished. 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed disease that is associated with the development of liver disease in adults and children and pulmonary emphysema in adults. Several studies have shown that there is limited knowledge about the disease and its diagnosis among health care providers, and there is an important inequity in the access to specialized care and appropriate treatment across Europe. The European Commision and the European Respiratory Society (ERS) recommend that the care of patients with AATD must be organized in reference centers at national or regional levels. These reference centers must provide optimal clinical care in terms of adequate diagnostic techniques, such as phenotyping and genotyping, and ensure access to treatment according to guidelines. Reference centers should also provide continuous medical education for health care professionals, genetic counseling, collaboration with patient associations and promote collaborative research and clinical trials with new and existing treatments for the disease. These centers must have a registry of their activity and collaborate with large, international, multicenter registries, such as the European Alpha-1 antitrypsin Deficiency Research Collaboration (EARCO) international registry, which is endorsed by the ERS, and aims to recruit up to 3,000 patients over a period of three years and prospectively follow them to better understand the natural history of the disease and the impact of different treatments on outcomes in a real life setting. International collaboration and standardized collection of high-quality prospective data will provide new insights into the clinical manifestations and prognosis of AATD.

The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.

Alpha-1 antitrypsin deficiency is an autosomal co-dominant inherited disorder that results in decreased circulating levels of alpha-1 antitrypsin (also known as alpha-1 proteinase inhibitor) and predisposes affected individuals to early onset lung and liver disease. There is currently no cure for alpha-1 antitrypsin deficiency. However, appropriate treatment and a high standard of clinical care can prevent patients from being seriously affected and having to undergo major medical interventions, such as organ transplantation. Beyond managing the symptoms associated with alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor therapy is the only treatment for the condition's underlying cause. Early diagnosis is important to ensure efficient therapeutic strategies and to minimize further deterioration of lung function. alpha-1 antitrypsin deficiency is under diagnosed globally, partly because the disease has no unique presenting symptoms. This document was prepared by a Portuguese multidisciplinary group and it aims to set out comprehensive principles of care for Alpha-1 antitrypsin deficiency. These include the importance of registries, the need for clinical research, the need for consistent recommendations (regarding diagnosis, treatment and monitoring), the role of reference centres, the requirement for sustained access to treatment, diagnostic and support services, and the role of patient organizations.

Alpha 1-antitrypsin (AAT) deficiency arises from an inherited mutation in the SERPINA1 gene. The disease causes damage in the liver where the majority of the AAT protein is produced. Lack of functioning circulating AAT protein also causes uninhibited elastolytic activity in the lungs leading to AAT deficiency-related emphysema. The only therapy apart from liver transplantation is augmentation with human AAT protein pooled from sera, which is only reserved for patients with advanced lung disease caused by severe AAT deficiency. We tested modified mRNA encoding human AAT in primary human hepatocytes in culture, including hepatocytes from AAT deficient patients. Both expression and functional activity were investigated. Secreted AAT protein increased from 1,14 to 3,43 µg/ml in media from primary human hepatocytes following mRNA treatment as investigated by ELISA and western blot. The translated protein showed activity and protease inhibitory function as measured by elastase activity assay. Also, mRNA formulation in lipid nanoparticles was assessed for systemic delivery in both wild type mice and the NSG-PiZ transgenic mouse model of AAT deficiency. Systemic intravenous delivery of modified mRNA led to hepatic uptake and translation into a functioning protein in mice. These data support the use of systemic mRNA therapy as a potential treatment for AAT deficiency.

Introduction: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy., Methods: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5)., Results: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R 2 =0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001)., Discussion: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy - the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD., Competing Interests: Professor Joanna Chorostowska-Wynimko reports grants, personal fees, non-financial support from Grifols, Boehringer Ingelheim, and CSL Behring, personal fees, non-financial support from Novartis, and personal fees from GSK, outside the submitted work. Dr Miriam Barrecheguren reports personal fees from Grifols, Menarini, CSL Behring, GSK, Novartis, and Gebro Pharma, outside the submitted work. Dr Ilaria Ferrarotti reports personal fees from Grifols and grants from CSL Behring, outside the submitted work. Dr Timm Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, and Novartis, outside the submitted work. Professor Robert A Sandhaus reports participation in advisory boards for Grifols, CSL Behring, AstraZeneca, Mereo, and Inhibrx for which he receives reimbursement of travel expenses. Dr Michael Campos reports grants, non-financial support, and personal fees from CSL Behring, and grants and personal fees from Grifols, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Chorostowska-Wynimko et al.)

Alpha-1 Antitrypsin Deficiency (AATD) is a progressive pulmonary disease under-recognized or misdiagnosed by clinicians. Patients with AATD can develop a variety of organ-specific complications and as a result, often require hospitalization and treatment within critical care and ICU settings. Due to the complexity of AATD there are minimal guidelines in place to address the specific and highly variable needs of these patients in the critical care setting. This review presents clinical considerations with respect to the management of patients with AATD and provides treatment recommendations for these patients in the critical care setting. In addition, we have outlined certain aspects of the care of this patient population that may be of interest to critical care practitioners. With greater disease awareness and earlier diagnosis the onset of symptoms can be delayed, which will ultimately reduce the frequency of deleterious health consequences., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Practice guidelines (PGs) attempt to standardize practice to optimize care. For uncommon lung diseases like alpha-1 antitrypsin deficiency (AATD), a paucity of definitive studies and geographic variation in prevalence may hamper guideline generation. The current study assembled and assesses the degree of concordance among available PGs regarding AATD., Methods: To assess concordance, 15 eligible guidelines focused on AATD were evaluated regarding recommendations surrounding 24 key clinical issues. A Delphi process achieved consensus on ratings for each statement among 3 reviewers. Agreement was quantified as the proportion of guideline comparisons with a matching rating., Results: The overall level of agreement was 47% (1190/2520 comparisons). The overall "affirmative agreement percentage" (ie, when guidelines agreed in endorsing a practice), was 42% (501/1190 comparisons). The agreement for individual clinical statements ranged from 26% to 75%. A broad consensus was seen in the recommendation to test all patients with a history of fixed obstruction on pulmonary function testing (either from asthma or COPD). Given that AATD is an under-recognized disease and that diagnosis often occurs at a late stage, the authors are encouraged by this consensus. Where overall the guidelines were less explicit was when to refer to a specialist or AATD center. Deciding on a treatment strategy requires a thorough understanding of the alpha 1 serum level, genotype, pulmonary function testing, and imaging, and therefore the authors feel that all patients would benefit from a specialty referral if the diagnosis of AATD is being considered., Conclusion: Available guidelines regarding AATD frequently disagreed in management recommendations. Possible explanations for discordance include differences in regional prevalence, availability of augmentation therapy, and insurance environments. Attempts to harmonize the various guidelines by empaneling a broadly representative international group of disease experts should be considered for AATD. Similar comparisons among guidelines for other diseases are recommended., Competing Interests: Dr Robert A Sandhaus served in Advisory Board for Grifols, CSL Behring, and Shire, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Attaway et al.)

Background and aim: The value of the forced expiratory volume in one second (FEV 1 ) is useful in the diagnosis and prognosis of chronic obstructive pulmonary disease (COPD). Previous studies on lung function in individuals with severe alpha-1 antitrypsin deficiency (AATD) have shown a variable annual decline in FEV 1 (∆FEV 1 ). The aim of this study was to analyze ∆FEV 1 and to identify risk factors for ∆FEV 1 in individuals with severe AATD. Material and methods: Data on smoking habits, symptoms, results of lung function tests and exacerbations were obtained from the Swedish AATD Register and the Swedish National Patient Register (SNPR). The ∆FEV 1 was analyzed by random-effects modeling and adjusted for age and FEV 1 at baseline. Results: One hundred and four (9%) current smokers, 539 (48%) ex-smokers and 489 (43%) never-smokers were included in the study and followed-up from 1991 to 2016. A total of 584 (52%) individuals with severe AATD had COPD at inclusion. The median (IQR) annual severe exacerbation rate was 0.66 (1.4). The adjusted mean ∆FEV 1 was significantly higher in the current smokers compared with the ex-smokers and never-smokers (70 [95% CI 56-83] vs 42 [95% CI 36-48] and 32 [95% CI 25-38) mL·yr -1 ], in the middle-aged individuals compared with the young individuals (48 [95% CI 41-55] vs 32 [95% CI 18-45] mL·yr -1 ), in the individuals with respiratory symptoms at inclusion compared with the asymptomatic individuals (46 [95% CI 40-52] vs 30 [95% CI 22-38]mL·yr -1 ), and in the individuals with frequent exacerbations compared with those with infrequent exacerbations (57 [95% CI 47-68] vs 27 [95% CI 17-37] mL·yr -1 ). Conclusion: Active smoking, age, respiratory symptoms at baseline and repeated severe exacerbations of COPD are factors associated with an accelerated decline of lung function in individuals with severe AATD., Competing Interests: The authors alone are responsible for the content and writing of the paper. The authors report no conflicts of interest in this work.

Importance: Alpha1-antitrypsin (AAT) deficiency is a common, but an underdiagnosed genetic condition, affecting 1 in 1500 individuals. It can present insidiously with liver disease in children. Although clinical practice guidelines exist for the management of AAT deficiency, especially with regards to pulmonary involvement, there are no published recommendations that specifically relate to the management of the liver disease and monitoring for lung disease associated with this condition, particularly in children., Objective: To review the literature on the management of AAT deficiency-associated liver disease in adults and children., Evidence Review: A systematic search for articles indexed in PubMed and published was undertaken. Some earlier selected landmark references were included in the review. Search terms included: "alpha1-antitrypsin deficiency"; "liver disease"; "end-stage liver disease"; "liver transplantation" and "preventative management". Recommendations for the management of children with suspected or confirmed AAT deficiency were made according to the Strength of Recommendation Taxonomy scale., Findings: Liver complications arising from AAT deficiency result from the accumulation of mutated AAT protein within hepatocytes. Liver disease occurs in 10% of children, manifested by cholestasis, pruritus, poor feeding, hepatomegaly, and splenomegaly, but the presentation is highly variable. A diagnostic test for AAT deficiency is recommended for these children. Baseline liver function tests should be obtained to assess for liver involvement; however, the only curative treatment for AAT deficiency-associated liver disease is organ transplantation. Conclusion and Relevance: There should be a greater vigilance for AAT deficiency testing among pediatricians. Diagnosis should prompt assessment of liver involvement. Children with AATdeficiency- associated liver disease should be referred to a liver specialist and monitored throughout their lifetimes for the symptoms of AAT-deficiency-related pulmonary involvement., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alpha-1-antitrypsin deficiency (AATD) is a genetic autosomal codominant disorder caused by mutations in SERPINA1 gene. It is one of the most prevalent genetic disorders, although it remains underdiagnosed. Whereas at international level there are several areas of consensus on this disorder, in Portugal, inter-hospital heterogeneity in clinical practice and resources available have been adding difficulties in reaching a diagnosis and in making therapeutic decisions in this group of patients. This raised a need to draft a document expressing a national consensus for AATD. To this end, a group of experts in this field was created within the Portuguese Pulmonology Society - Study group on AATD, in order to elaborate the current manuscript. The authors reviewed the existing literature and provide here general guidance and extensive recommendations for the diagnosis and management of AATD that can be adopted by Portuguese clinicians from different areas of Medicine. This article is part of a supplement entitled "Portuguese consensus document for the management of alpha-1-antitrypsin deficiency" which is sponsored by Sociedade Portuguesa de Pneumologia., (Copyright © 2018. Published by Elsevier España, S.L.U.)

Endobronchial coil treatment (ECT) is a minimally invasive procedure developed for palliative care of patients with severe emphysema. ECT has demonstrated a decrease in hyperinflation, an improvement in quality of life, and an acceptable safety profile in randomized controlled trials (RCTs). Because alpha-1 antitrypsin deficiency (AATD) is a classical exclusion criterion in RCTs, there is no available data for ECT in AATD. In this post hoc analysis of the REVOLENS study (Réduction volumique endobronchique par spirales; ClinicalTrials.gov Identifier: NCT01822795), a multicenter 1:1 RCT which compared bilateral ECT with usual care in severe emphysema, we analyzed the efficacy and safety results at 1 year in six patients with AATD (five males, one female; mean age: 52±9 years) who underwent ECT. A significant decrease in hyperinflation (0.35 L decrease in residual volume [RV]) was observed in four out of six patients at 6 months and three out of six patients at 12 months, and an improvement in quality of life (improvement of 4 points in the St George's Respiratory Questionnaire [SGRQ]) was observed in four out of six patients at both 6 and 12 months. Efficacy results at 6 and 12 months from the six AATD patients were compared with 84 non-AATD patients who underwent ECT, and no statistically significant differences were found for FEV 1 , RV, 6MWT score and SGRQ score. Respiratory-related serious adverse event was limited to pneumonia in one AATD patient at 1 year post-ECT. This post hoc study suggests that AATD patients may have similar efficacy and safety outcomes at 1 year as non-AATD patients. Because of the paucity of available data, appropriately powered studies are needed to determine the effects of ECT in AATD., Competing Interests: Disclosure Gaëtan Deslee has been involved as an investigator in previous studies sponsored by BTG/PneumRx, and received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. Hervé Mal received honorarium from Boehringer, Bayer, Roche, Astellas, Chiesi, Actellion, Pfizer, Novartis, and GlaxoSmithKline outside the submitted work. Hervé Dutau received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. Arnaud Bourdin received honorarium from Astra Zeneca, GlaxoSmithKline, Boehringer, Novartis, Teva, Chiesi, Actellion, Gilead, and Roche outside the submitted work. Jean Michel Vergnon received travel reimbursements and speaker fees for educational sessions from BTG/PneumRx. Christophe Pison received honorarium from BTG/PneumRx and his hospital received funds to conduct trials from Holaira, PulmonX, and BTG/PneumRx. Charles Hugo Marquette has been involved as an investigator in previous studies sponsored by BTG/PneumRx, and received travel reimbursements and speaker fees for educational sessions and consulting from BTG/PneumRx. The authors report no other conflicts of interest in this work.

In homozygous ZZ alpha-1-antitrypsin (AAT) deficiency, the liver synthesizes large quantities of AAT mutant Z, which folds improperly during biogenesis and is retained within the hepatocytes and directed into intracellular proteolysis pathways. These intracellular polymers trigger an injury cascade, which can lead to liver injury. This is highly variable and not all patients develop liver disease. Although not fully described, there is likely a strong influence of genetic and environmental modifiers of the injury cascade and of the fibrotic response. With improved understanding of liver injury mechanisms, new strategies for treatment are now being explored., (Copyright © 2018 Elsevier Inc. All rights reserved.)