The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Ronald G. Crystal - One of the best experts on this subject based on the ideXlab platform.
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intrapleural gene therapy for Alpha 1 antitrypsin deficiency related lung disease
Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation, 2018Co-Authors: Katie M Stiles, Dolan Sondhi, Stephen M Kaminsky, Jonathan B Rosenberg, Ronald G. CrystalAbstract:Alpha-1 antitrypsin deficiency (AATD) manifests primarily as early-onset emphysema caused by the destruction of the lung by neutrophil elastase due to low amounts of the serine protease inhibitor Alpha-1 antitrypsin (AAT). The current therapy involves weekly intravenous infusions of AAT-derived from pooled human plasma that is efficacious, yet costly. Gene therapy applications designed to provide constant levels of the AAT protein are currently under development. The challenge is for gene therapy to provide sufficient amounts of AAT to normalize the inhibitor level and anti-neutrophil elastase capacity in the lung. One strategy involves administration of an adeno-associated virus (AAV) gene therapy vector to the pleural space providing both local and systemic production of AAT to reach consistent therapeutic levels. This review focuses on the strategy, advantages, challenges, and updates for intrapleural administration of gene therapy vectors for the treatment of AATD.
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Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease.
Annals of the American Thoracic Society, 2016Co-Authors: Maria J. Chiuchiolo, Ronald G. CrystalAbstract:Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT gene therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT gene therapy to the bedside.
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Alpha 1 antitrypsin augmentation therapy
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2013Co-Authors: Mark D Wewers, Ronald G. CrystalAbstract:AbstractThe therapy of Alpha-1 antitrypsin deficiency (AATD) is an example of a medical triumph over a common hereditary disease. Based on the understanding of the pathogens of the disease as a deficiency in liver production of Alpha-1 antitrypsin (AAT) resulting from inherited genetic variation in both parental AAT genes, the knowledge that A1AT functions primarily to inhibit neutrophil elastase (NE), and the observation that NE instilled into the lung of experimental animals resulted in emphysema, the concept evolved that the pulmonary manifestations of the disease could be halted by intermittent intravenous infusions of AAT purified from pooled human plasma. Following preliminary clinical studies in the academic community, and then pharmaceutical company development of large scale purification of human AAT, the FDA approved the use of weekly AAT augmentation therapy for AATD following a clinical trial which demonstrated that weekly infusions would raise to normal plasma and lung epithelial fluid levels...
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intraperitoneal in vivo gene therapy to deliver Alpha 1 antitrypsin to the systemic circulation
American Journal of Respiratory Cell and Molecular Biology, 1994Co-Authors: Yasuhiro Setoguchi, H A Jaffe, C S Chu, Ronald G. CrystalAbstract:The utility of replication-deficient recombinant adenovirus vector-mediated transfer and expression of the Alpha 1-Antitrypsin (Alpha 1AT) cDNA to peritoneal mesothelial tissues was evaluated as a means of delivering Alpha 1AT to the systemic circulation. Preliminary studies with Ad.RSV beta gal, an adenovirus vector expressing the Escherichia coli lacZ gene (beta-galactosidase), showed that intraperitoneal injection of 10(9) plaque-forming units (pfu) to cotton rats resulted in beta-galactosidase activity in mesothelial cells lining the peritoneal cavity. After intraperitoneal administration of 10(9) pfu of Ad Alpha 1AT (an adenovirus vector containing the human Alpha 1AT cDNA), human Alpha 1AT was detectable in serum for up to 24 days, with a maximal level of 3.4 micrograms/ml at 4 days. Expression of the exogenous gene was localized to the peritoneal mesothelium as PCR analyses detected no evidence of expression of the exogenous gene in any other tissues evaluated. Anti-adenovirus vector antibodies wer...
Mark L Brantly - One of the best experts on this subject based on the ideXlab platform.
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clinical and histologic features of adults with Alpha 1 antitrypsin deficiency in a non cirrhotic cohort
Journal of Hepatology, 2018Co-Authors: Virginia Clark, George Marek, Chen Liu, Amy L Collinsworth, Jonathan J Shuster, Tracie L Kurtz, Joanna L Nolte, Mark L BrantlyAbstract:Background & Aims Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. Methods A total of 94 adults with classic genotype ‘PI*ZZ’ AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. Results The prevalence of clinically significant liver fibrosis (F ≥ 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7–55; p Conclusions Over one-third of asymptomatic and lung affected adults with ‘PI*ZZ’ AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a “toxic gain of function” from accumulation of AAT in hepatocytes. Lay summary Individuals diagnosed with classic Alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal Alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of Alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of Alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. Clinical Trial number clinicaltrials.gov NCT01810458.
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Alpha 1 antitrypsin deficient macrophages have increased matriptase mediated proteolytic activity
American Journal of Respiratory Cell and Molecular Biology, 2017Co-Authors: Karina Krotova, Farshid N Rouhani, George Marek, Rejean L Wang, George Aslanidi, Brad E Hoffman, Nazli Khodayari, Mark L BrantlyAbstract:Alpha-1 antitrypsin (AAT) deficiency–associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mɸ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mɸ. Importantly, ...
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the diagnosis and management of Alpha 1 antitrypsin deficiency in the adult
Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation, 2016Co-Authors: R A Sandhaus, Mark L Brantly, James M Stocks, Gerard M Turino, Michael A Campos, Carroll E Cross, Kenneth W Goodman, Douglas K Hogarth, Shandra L Knight, James K. StollerAbstract:Background: The diagnosis and clinical management of adults with Alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived Alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD.
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the challenge of detecting Alpha 1 antitrypsin deficiency
COPD: Journal of Chronic Obstructive Pulmonary Disease, 2013Co-Authors: James K. Stoller, Mark L BrantlyAbstract:Alpha-1 antitrypsin deficiency (AATD) is relatively common but under-recognized. Indeed, fewer than 10% of the estimated 100,000 Americans with AATD have been diagnosed currently, with common reports of long delays between initial symptoms and first detection and the need to see multiple physicians before diagnosis. Because detection can confer benefits (e.g., identification of at-risk family members, lower smoking likelihood, consideration of augmentation therapy), targeted detection of AATD in at-risk groups such as all symptomatic adults with COPD has been endorsed. Two general approaches to detection have been studied: population-based screening (in which testing is performed in a group for whom no increased risk of having AATD exists) and targeted detection or case-finding (in which testing is confined to those with an attributable condition such as COPD or chronic liver disease). Studies to date have suggested that population-based screening is not cost-effective, whereas targeted detection of AATD has been advocated by official society guidelines. Efforts to enhance detection of AATD individuals have included various approaches, including educational campaigns, provision of free test kits, issuance of reminders with medical reports or within an electronic medical record, and empowering respiratory therapists to conduct testing for AATD in pulmonary function laboratories. Such programs have identified individuals with severe deficiency of Alpha-1 antitrypsin in up to 12% of subjects, with considerable variation across series by testing criteria. Overall, the persistence of under-recognition of AATD underscores the need for continued efforts to optimize detection of this potentially debilitating genetic disease.
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Alpha 1 antitrypsin augmentation therapy in deficient individuals enrolled in the Alpha 1 foundation dna and tissue bank
International Journal of Chronic Obstructive Pulmonary Disease, 2009Co-Authors: Adriano R Tonelli, Pam Schreck, Farshid N Rouhani, Ning Li, Mark L BrantlyAbstract:INTRODUCTION: Intravenous augmentation therapy with purified intravenous Alpha-1 antitrypsin replaces the deficient protein and is the only currently approved treatment for Alpha-1 antitrypsin deficiency (AATD) related lung disease. While augmentation therapy has been available for more than 20 years, there are a limited number of studies evaluating the effect of augmentation on lung function. MATERIAL AND METHODS: We examined the decline in forced expiratory volume in one second (FEV(1)) in patients enrolled in the Alpha-1 Foundation DNA and Tissue Bank in relation to the use or not of Alpha-1 antitrypsin augmentation therapy. For the purpose of our analysis we included 164 patients with AATD and PI ZZ genotype. RESULTS: Mean age of the patients was 60 years, 52% were females, 94% were white and 78% ex-smokers. The mean FEV(1) at baseline was 1.7 L and the mean FEV(1) % of predicted was 51.3%. The mean follow-up time was 41.7 months. A total of 124 (76%) patients received augmentation therapy (augmented group) while 40 patients (24%) did not received it (non-augmented group). When adjusted by age at baseline, sex, smoking status, baseline FEV(1) % of predicted, the mean overall change in FEV(1) was 47.6 mL/year, favoring the augmented group (DeltaFEV(1) 10.6 +/- 21.4 mL/year) in comparison with the non-augmented group (DeltaFEV(1) -36.96 +/- 12.1 mL/year) (P = 0.05). Beneficial DeltaFEV(1) were observed in ex-smokers and the group with initial FEV(1) % of predicted of <50%. No differences were observed in mortality. CONCLUSIONS: In conclusion, augmentation therapy improves lung function in subjects with AATD when adjusted by age, gender, smoking status and baseline FEV(1) % of predicted. The beneficial effects were noted in ex-smoker subjects with FEV(1) below 50% of predicted.
Alice M Turner - One of the best experts on this subject based on the ideXlab platform.
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the european Alpha 1 research collaboration earco a new ers clinical research collaboration to promote research in Alpha 1 antitrypsin deficiency
European Respiratory Journal, 2019Co-Authors: Marc Miravitlles, Robert A Stockley, Joanna Chorostowskawynimko, Ilaria Ferrarotti, Noel G Mcelvaney, Karen Ohara, Jan Stolk, Alice M Turner, Marion Wilkens, Timm GreulichAbstract:The European Alpha-1 Research Collaboration (EARCO) will promote international research in Alpha-1 antitrypsin deficiencyhttp://ow.ly/DWwg30nwCj4
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hepatic targeted rna interference provides robust and persistent knockdown of Alpha 1 antitrypsin levels in zz patients
Journal of Hepatology, 2018Co-Authors: Alice M Turner, Jan Stolk, Robert Bals, J Lickliter, J Hamilton, D Christianson, Bruce D Given, Jonathan Burdon, Rohit Loomba, James K. StollerAbstract:Background & Aims Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT ( SERPINA1 ) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. Methods Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) Results A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. Conclusion PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. Lay summary Accumulation of abnormal proteins in the livers of patients with Alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with Alpha-1 antitrypsin deficiency. Clinical Trial Registration Number: NCT02363946.
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treatment of lung disease in Alpha 1 antitrypsin deficiency a systematic review
International Journal of Chronic Obstructive Pulmonary Disease, 2017Co-Authors: Alice M Turner, Ross Edgar, Mitesh Patel, Susan Bayliss, Diana Crossley, Elizabeth SapeyAbstract:BACKGROUND Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. METHODS Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. RESULTS In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved Alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. CONCLUSION Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.
Noel G Mcelvaney - One of the best experts on this subject based on the ideXlab platform.
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clarifying the risk of lung disease in sz Alpha 1 antitrypsin deficiency
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Alessandro N Franciosi, Brian D Hobbs, Oliver J Mcelvaney, Kevin Molloy, Craig P Hersh, Louise Clarke, Cedric Gunaratnam, Edwin K Silverman, Tomas P Carroll, Noel G McelvaneyAbstract:Rationale: The ZZ genotype of Alpha-1 antitrypsin deficiency (AATD) is associated with chronic obstructive pulmonary disease (COPD), even among never-smokers. The SZ genotype is also considered sev...
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the european Alpha 1 research collaboration earco a new ers clinical research collaboration to promote research in Alpha 1 antitrypsin deficiency
European Respiratory Journal, 2019Co-Authors: Marc Miravitlles, Robert A Stockley, Joanna Chorostowskawynimko, Ilaria Ferrarotti, Noel G Mcelvaney, Karen Ohara, Jan Stolk, Alice M Turner, Marion Wilkens, Timm GreulichAbstract:The European Alpha-1 Research Collaboration (EARCO) will promote international research in Alpha-1 antitrypsin deficiencyhttp://ow.ly/DWwg30nwCj4
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the prevalence of Alpha 1 antitrypsin deficiency in ireland
Respiratory Research, 2011Co-Authors: Tomas P Carroll, Catherine Oconnor, Olwen Floyd, Joseph Mcpartlin, Dermot Kelleher, Geraldine Obrien, Borislav D Dimitrov, Valerie B Morris, Clifford C Taggart, Noel G McelvaneyAbstract:Background Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients.
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development of predictive models for airflow obstruction in Alpha 1 antitrypsin deficiency
American Journal of Epidemiology, 2009Co-Authors: Peter J Castaldi, Mark L Brantly, Noel G Mcelvaney, Dawn L Demeo, Edward Eden, Stephen I Rennard, David M Kent, Edward J Campbell, A J Barker, James M StocksAbstract:Alpha-1-Antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV1 and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV1 explained 50% of the variance in FEV1, and the model for severe COPD exhibited excellent discrimination (c statistic ¼ 0.88). Alpha-1-Antitrypsin deficiency; genetics; polymorphism, single nucleotide; pulmonary disease, chronic obstructive
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Gene targeted therapeutics for liver disease in Alpha-1 antitrypsin deficiency
Dove Medical Press, 2009Co-Authors: Caitriona Mclean, Catherine M Greene, Noel G McelvaneyAbstract:Caitriona McLean*, Catherine M Greene*, Noel G McElvaneyRespiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; *Each of these authors contributed equally to this workAbstract: Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.Keywords: Alpha-1 antitrypsin deficiency, siRNA, peptide nucleic acid, ribozyme
Ross Edgar - One of the best experts on this subject based on the ideXlab platform.
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treatment of lung disease in Alpha 1 antitrypsin deficiency a systematic review
International Journal of Chronic Obstructive Pulmonary Disease, 2017Co-Authors: Alice M Turner, Ross Edgar, Mitesh Patel, Susan Bayliss, Diana Crossley, Elizabeth SapeyAbstract:BACKGROUND Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. METHODS Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. RESULTS In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved Alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. CONCLUSION Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.
