Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Lόpez-Campos, José Luís; Hernández, Laura Carrasco; Eraso, Candelaria Caballero

doi:10.3390/jcm9082526

Cited by 13 publications

(11 citation statements)

References 83 publications

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“…Modes of therapy administration include self-infusion, aerosol, and subcutaneous administration. Gene and recombinant therapies are under development [188,189], and intravenous therapy using α1 antitrypsin derived from human donor plasma has proven to be safe [187].…”

Section: Treatments and New Therapeutic Approachesmentioning

confidence: 99%

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

et al. 2021

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Chronic obstructive pulmonary disease (COPD) is one of the leading global causes of morbidity and mortality. A hallmark of COPD is progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. Different cell types, including macrophages, epithelial cells, neutrophils, and T lymphocytes, contribute to COPD pathophysiology. Alteration in cell functions results in the generation of an oxidative and inflammatory microenvironment, which contributes to disease progression. Current treatments include inhaled corticosteroids and bronchodilator therapy. However, these therapies do not effectively halt disease progression. Due to the complexity of its pathophysiology, and the risk of exacerbating symptoms with existing therapies, other specific and effective treatment options are required. Therapies directly or indirectly targeting the oxidative imbalance may be promising alternatives. This review briefly discusses COPD pathophysiology, and provides an update on the development and clinical testing of novel COPD treatments.

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Section: Treatments and New Therapeutic Approachesmentioning

confidence: 99%

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

et al. 2021

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“…Intravenous augmentation therapy with pAAT has, to date, been the only specific treatment for AATD patients with advanced emphysema (3,4). However, studies revealed only modest effects of this therapy; this treatment slowed progression of emphysema as measured by lung density with computed tomography or total lung capacity, but not when measured by functional residual capacity (29).…”

Section: Discussionmentioning

confidence: 99%

“…Exogenous repletion of AAT, "augmentation therapy", is recommended for select patients with emphysema, with weekly intravenous infusions of AAT purified from pooled human plasma (pAAT) (3 ,4). However, only modest clinical benefits of augmentation therapy have been reported, and these infusions have been associated with side effects related to infusion of high amounts of protein (3,4). In addition, augmentation therapy is recognized as inconvenient because of the need for frequent infusions and high costs (3,5).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Benefits of Recombinant Alpha1-Antitrypsin IgG1 Fc-Fusion Protein in Experimental Emphysema

Takeda

Kim

Joetham

et al. 2021

Preprint

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BackgroundAlpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), “augmentation therapy”, provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. MethodsIn an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo . ResultsBoth elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNg and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4 + T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNg and IL-17. ConclusionsCompared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.

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“…Interestingly, the determination of AAT in peripheral blood has some technical conditions that are relevant when interpreting the results well. However, many investigators do not take these differences into account and it is generally assumed that the determination of AAT in blood is equally valid regardless of the laboratory method used [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

Ruiz-Duque

Bañuls

Reinoso-Arija

et al. 2021

JCM

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Background: The study of hematic concentrations of alpha1 antitrypsin (AAT) is currently one step in the diagnosis of AAT deficiency. To try to clarify the relevance of the laboratory techniques, we carried out a systematic review of the literature. Methods: Studies evaluating the quantification of AAT in peripheral blood were searched in PubMed in July 2021. The selection criteria included (1) any type of study design that included a quantification of AAT in peripheral blood; (2) studies written in English or Spanish; (3) studies evaluating human beings; and (4) studies involving adults. Results: Out of 207 studies, the most frequently used techniques were nephelometry (43.9%), followed by ELISA (19.8%) and turbidimetry (13.5%). Altogether, 182 (87.9%) cases expressed their results in units of gram, while 16 (7.7%) articles expressed them in units of mole. Only 2.9% articles referred to the standard used, 43.5% articles indicated the commercial kit used, and 36.2% indicated the analyzer used. Conclusions: The technical aspects of these determinations are not always reported in the literature. Journals should be attentive to these technical requirements and ensure that they are included in the works in which AAT is determined in order to ensure a correct interpretation of the study findings.

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Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Cited by 13 publications

References 83 publications

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

Therapeutic Benefits of Recombinant Alpha1-Antitrypsin IgG1 Fc-Fusion Protein in Experimental Emphysema

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

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