Treatment Of Alpha-1 Antitrypsin Deficiency Research Articles

Alpha 1-antitrypsin deficiency

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.

European pathways of care in Alpha-1 Antitrypsin deficiency

BackgroundDespite initiatives to improve awareness and treatment of alpha-1 antitrypsin deficiency (AATD), country-level processes for AATD management remain unclear. ObjectivesWe conducted a pan-European physician survey to clarify the pathways for AATD care. MethodProfessionals 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). ResultsSurveys 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. ConclusionsEuropean 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.

But I Still Can’t Breathe!: A Case Challenge

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that can cause life-threatening lung and liver damage and occasionally affects the skin. When it affects the lungs, it leads to early-onset chronic obstructive pulmonary disease. Alpha-1 antitrypsin, a protease inhibitor, is a defensive protein produced in the liver that protects the lungs from a powerful enzyme called neutrophil elastase. The inequality of alpha-1 antitrypsin to neutrophil elastase causes progressive degenerative damage to the lung. AATD often goes undiagnosed or misdiagnosed because of a lack of awareness of the disorder and because it has similar clinical features as asthma. Early identification and treatment of AATD are essential to preventing irreversible lung damage, respiratory failure, and even death.

How are we in Brazil with the treatment of alpha-1 antitrypsin deficiency?

How are we in Brazil with the treatment of alpha-1 antitrypsin deficiency?

Alpha-1 Antitrypsin Deficiency: Home Therapy.

While available in only a few countries, home therapy is a possible strategy for the treatment of alpha-1 antitrypsin deficiency. We want to describe our experience in the management of human alpha-1 antitrypsin using home care intravenous augmentation therapy during this emergency period caused by SARS-CoV2 infection. We assessed the safety of the home treatment and the quality of life of patients enrolled in the program.

Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives.

This review summarizes the current research and outlooks regarding the obstacles to diagnosing and treating early alpha-1-antitrypsin deficiency (AATD). It draws on prior systematic reviews and expert surveys to discover precisely what difficulties exist in early diagnosis and treatment of AATD and elucidate potential solutions to ease these difficulties. The perceived rarity of AATD may translate to a condition poorly understood by primary care physicians, and even many respiratory physicians, which results in opportunities for diagnosis being missed, especially in mild or asymptomatic patients. There are diagnostic techniques involving biomarkers and home testing methods which could improve the rate of early diagnosis. With respect to treatment, AATD involves treating two separate pathologies, lung disease and liver disease. The only specific AATD treatment, augmentation therapy, has proven ability in treating lung disease but not liver disease. Alpha-1-antitrypsin (AAT) synthesized in the liver can form damaging polymers that also result in reduced circulating AAT levels and, whilst liver transplantation is used to effectively treat AATD, it is inappropriate in early disease. Novel therapeutic areas such as gene editing and increasing autophagy are therefore being researched as future treatments. Ultimately, diagnosis and treatment are intrinsically linked in AATD, with earlier diagnosis leading to better treatment options and thus better patient outcomes.

Engineering synthetic breath biomarkers for respiratory disease.

Human breath contains many volatile metabolites. However, few breath tests are currently used in the clinic to monitor disease due to bottlenecks in biomarker identification. Here we engineered breath biomarkers for respiratory disease by local delivery of protease-sensing nanoparticles to the lungs. The nanosensors shed volatile reporters upon cleavage by neutrophil elastase, an inflammation-associated protease with elevated activity in lung diseases such as bacterial infection and alpha-1 antitrypsin deficiency. After intrapulmonary delivery into mouse models with acute lung inflammation, the volatile reporters are released and expelled in breath at levels detectable by mass spectrometry. These breath signals can identify diseased mice with high sensitivity as early as 10 min after nanosensor administration. Using these nanosensors, we performed serial breath tests to monitor dynamic changes in neutrophil elastase activity during lung infection and to assess the efficacy of a protease inhibitor therapy targeting neutrophil elastase for the treatment of alpha-1 antitrypsin deficiency.

Identification of small molecules by screening a mixture-based scaffold compound library for treatment of alpha-1 antitrypsin deficiency

This study aimed to identify small molecules that have the potential to treat alpha1-antitrypsin deficiency (AATD) by screening compounds available from a mixture-based scaffold library. 93 scaffold libraries (total diversity of >30 million compounds in mixture format) were screened using a cell model of AATD in order to identify samples that could either reduce intracellular aggregation of Z-form AAT protein, increase extracellular secretion of Z-AAT or both. Mixture libraries containing compounds with in vitro activity, for example library 1295, were screened further to identify individual active compounds. The mixture format of the scaffold library allowed for some preliminary structure-activity relationships to be developed and also enabled the rapid selection of a promising scaffold. Utilizing this scaffold, 1295, a collection of individual “control” compounds contained in the 1295 mixture sample were then screened. A sub-library of individual “control” compounds featuring structural diversity at position R1 (1295.R1), was screened and 7 compounds were found to reduce the intracellular accumulation of Z-AAT without affecting cell viability at a concentration of 25ug/ml (about 50 μM). Screening sub-libraries featuring structural diversity at R2 and R3 (1295.R2 and 1295.R3) identified an additional 15 active compounds. Titration experiments identified 3 compounds from the 1295.R2 library that retained activity at 5ug/ml (approx. 10uM). One compound (1295.263) from 1295.R2 decreased intracellular levels of Z-AAT without affecting cell viability and wild-type AAT levels at the concentration of 5ug/ml. Molecular docking of this compound to the Z-AAT crystal structure identified a potential binding site near the C-terminal domain, an identified polymerization site. Our results indicate that screening large mixture-based compound libraries can be used to identify small molecules that may have the potential to treat AATD and other disease.

181. Optimization of In Vivo Delivery of Baculovirus Gene Therapy Vectors for the Treatment of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a single-gene disorder commonly associated with adult onset lung diseases, including emphysema, chronic obstructive pulmonary disease and airway inflammation. Alpha-1 antitrypsin (AAT) is produced primarily in hepatocytes and is subsequently secreted into the bloodstream and travels to the lung where it inhibits neutrophil elastase. Unregulated neutrophil elastase activity in individuals with AATD causes degradation of various components of the extracellular matrix producing damage to alveolar and airway epithelial cells. Furthermore, mutated AAT folds incorrectly causing intracellular aggregation within hepatocytes, which can result in liver damage in addition to pulmonary symptoms. The development of gene therapy strategies has been a popular approach for the treatment of AATD due to monogenic nature of this genetic disease. Recently, baculovirus based vectors have garnered attention for possible application in gene therapy due to multiple factors. Baculoviruses can tolerate large gene insertions (>38kb), are capable of transducing mammalian cells but not replicating or integrating into host chromosomes and finally, humans lack pre-existing immunity to these insect viruses. Although there are many characteristics that make baculovirus vectors attractive for use in gene therapy, there is little in vivo data on bio-distribution and tissue tropism in mammalian models. As AATD is a disease affecting both the liver and the lung, we examined several delivery routes of a baculovirus vector expressing the human placental alkaline phosphatase reporter gene in C57BL/6 mice. To target the lung we investigated intranasal and intratracheal administration and for liver delivery intravenous, intrahepatic and intraportal vein injections were utilized. Lung delivery of wild type baculovirus yielded little transduction, however intrahepatic injection resulted in moderate liver transduction as well as unexpected spread to other tissues. Different formulations of the baculovirus vector were examined for pulmonary delivery including a variety of viscoeleastic gels. Additionally, pharmacological agents such as clodronate liposomes to deplete macrophages and cobra venom factor to ablate complement activity were examined in an effort to bolster transduction.

Practice and knowledge about diagnosis and treatment of alpha-1 antitrypsin deficiency in Spain and Portugal

BackgroundDetermining physicians’ awareness about alpha-1 antitrypsin (AAT) deficiency (AATD) may help to explain the discrepancy between the observed and expected number of patients diagnosed with this disease.This study was designed to assess the opinions on knowledge, practice pattern and attitude regarding AATD among physicians in Spain and Portugal.MethodsAn online anonymous survey was performed on pulmonologists (n = 100), internal medicine specialists (IMS) (n = 100) and primary care physicians (PCP) (n = 176). Of the total number of physicians, 221 were from Spain, and 155 were from Portugal. Physicians answered 21 questions related to their personal and professional profile, knowledge regarding AATD and chronic obstructive pulmonary disease (COPD), performance and attitude about AATD, and use of augmentation therapy. Responses were ranked on a 4-point scale indicating the level of agreement. In addition, some of the responses were rated as either “low” or “high” indicating the level of knowledge the respondent felt he/she possessed.ResultsOnly 14 % of physicians reported to “know very well” about AATD (3.3 [SD 0.6] for pulmonologists vs. 2.64 [SD 0.60] for IMS and 2.48 [SD 0.71] for PCP; p < 0.001). Only 45.2 % of physicians correctly answered “<50 mg/dL” as the threshold value of serum AAT to be considered severe AATD (55.0 % of pulmonologists vs. 47.0 % of IMS and 38.6 % of PCP; p = 0.001). Choice of the correct answer did not agree with those physicians self-declaring a high level of AATD knowledge (51.2 %). A total of 43.9 % of physicians correctly identified all diseases or conditions in a list associated or not with AATD. A similar trend was detected when identifying which conditions would be responsive to augmentation therapy (<50 %). Only 15.8 % of specialists performed AATD testing in all patients with COPD (27.0 % pulmonologists, 12.6 % PCP; p = 0.001).ConclusionThe results suggest that a knowledge gap may be contributing to the underdiagnosis of AATD. Physicians in Spain and Portugal showed a marked lack of awareness of their shortcomings in knowledge about AATD, and in general did not follow guidelines and recommendations for AATD testing.

98. Bortezomib Enhances AAV Vector Mediated Transduction But Inhibits the Secretion of Transgene Product

Adeno-associated virus (rAAV) mediated gene therapy has shown promise for the treatment of alpha1 antitrypsin deficiency (AATD). Sustained alpha 1 antitrypsin (AAT) expression has been achieved in clinical trails, but the serum AAT concentrations do not reach therapeutic levels. Enhancing transduction efficiency is critical to developing a successful treatment. Since rAAV transduction may be limited by the proteasome, which degrade AAV capsids, we tested the effect of proteasome inhibitors on rAAV mediated AAT production. We treated HeLa and 293 cells with proteasome inhibitors including bortezomib and infected HeLa cells with rAAV2-GFP, rAAV2-AAT or AAV1-AAT and we Infected 293 cells with rAAV2-AAT. We measured AAT in the medium and the lysates of cells. Consistent with previous reports, bortezomib significantly enhanced AAV2 mediated GFP transduction in Hela cells. In rAAV-AAT infected cells, bortezomib treatment resulted in 9.7-13.1 fold increase in of intracellular AAT, while only modest (1.16-1.6 fold) increases of secreted AAT compared to that in cells without bortezomib. Similarly, intramuscular injection of rAAV1-AAT to C57BL6 mice treated with bortezomib also resulted in a small (~1 fold) increases in serum AAT compared with no treatment. These results indicate that bortezomib inhibited AAT protein secretion. To test the role unfolded protein response (UPR) in AAT accumulation, we measured UPR-related genes and showed that bortezomib treatment increased the mRNA levels of the protein chaperone and UPR sensor GRP78 (BiP) indicating an activation of ER stress pathways. Together, our results indicate that bortezomib can enhance rAAV transduction, but it can also inhibit the secretion of transgene product, which will limit the application of this drug for enhancing the efficiency of certain gene therapy, such as alpha 1 antitrypsin gene therapy.

Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes.

Alpha-1 antitrypsin (AAT) deficiency remains an underrecognized genetic disease with predominantly pulmonary and hepatic manifestations. AAT is derived primarily from hepatocytes; however, macrophages and neutrophils are secondary sources. As the natural physiological inhibitor of several proteases, most importantly neutrophil elastase (NE), it plays a key role in maintaining pulmonary protease–antiprotease balance. In deficient states, unrestrained NE activity promotes damage to the lung matrix, causing structural defects and impairing host defenses. The commonest form of AAT deficiency results in a mutated Z AAT that is abnormally folded, polymerized, and aggregated in the liver. Consequently, systemic levels are lower, resulting in diminished pulmonary concentrations. Hepatic disease occurs due to liver aggregation of the protein, while lung destruction ensues from unopposed protease-mediated damage. In this review, we will discuss AAT deficiency, its clinical manifestations, and augmentation therapy. We will address the safety and tolerability profiles of AAT replacement in the context of patient outcomes and cost-effectiveness and outline future directions for work in this field.

Inhaled Alpha 1-Antitrypsin: Gauging Patient Interest in a New Treatment

Background: Given the high cost of plasma derived intravenous alpha 1-antitrypsin (AAT), a more efficient method of delivery to the lungs is desirable. Inhaled AAT has been shown feasible for the treatment of alpha 1-antitrypsin deficiency (AATD) and is currently in clinical trials. To better understand patient preferences about possible inhaled AAT therapy, a survey was conducted to explore patient attitudes. Methods: We conducted an email based survey of patients in the Alpha-1 Foundation Research Registry with AATD on intravenous AAT replacement. Respondents were asked to rate their interest in hypothetical nebulized or dry powder inhaled AAT. Results: Respondents reported high levels of interest in both dried powder inhaler and nebulizer delivered inhaled AAT. The interest in dried powder inhaled was higher than interest in nebulized AAT (71% vs 64%, p = 0.0001). The interest in dried powder inhaled AAT was particularly high in respondents currently on bronchodilator therapy (p = 0.0053). Patients were just as likely to use or not use the product if it required 20% more out of pocket cost. Conclusions: There is a high level of patient interest in the development of a commercially available inhaled AAT replacement product.

The Promise of Gene Therapy For The Treatment of α-1 Antitrypsin Deficiency

In the last 13 years, three gene therapy trials for the treatment of alpha-1 antitrypsin deficiency have been conducted. The first trial delivered plasmid encoding the alpha-1 antitrypsin cDNA to the nasal epithelium using cationic liposomes. The last two trials delivered recombinant adeno-associated vectors encoding the alpha-1 antitrypsin cDNA by intramuscular injection. In this review, the progress of ongoing clinical trials and new gene therapy technologies is discussed.

Stem cell therapies in reparative medicine.

The future implementation of stem cell therapies to treat conditions thus far considered incurable has been envisioned as logical consequence of the fast-paced progress in stem cell research over the last few years. Still, many practical obstacles stand in the way to the routine application of these novel technologies in medicine. The conference "Stem Cell Therapies in Reparative Medicine," held aboard the cruise vessel Majesty of the Seas (Miami, USA-Nassau, Bahamas, April 19-22, 2002), focused on the analysis of these problems from different perspectives, including developmental biology (cell proliferation, fate determination, and enrichment), immunology (allorejection and prevention of autoimmunity recurrence), and clinical therapy, emphasizing the impact of stem cell technologies on the emerging field of tissue engineering and the treatment of alpha-1 antitrypsin deficiency.