Should Health-Care Systems Pay for Replacement Therapy in Patients With α1-Antitrypsin Deficiency?

Alkins, Stephan A.; O’Malley, Patrick G.

doi:10.1378/chest.117.3.875

Cited by 45 publications

(30 citation statements)

References 22 publications

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“…In the context that augmentation therapy is expensive (i.e., with estimated 2011 average annual wholesale prices of $93,000 to $120,000) (176), the question of cost-effectiveness has been addressed by several studies (177)(178)(179). Methodologic variation among these studies likely accounts for the substantial difference in cost-effectiveness estimates (Table E4) (177)(178)(179).…”

Section: Treatment Of Aatdmentioning

confidence: 99%

A Review of α₁-Antitrypsin Deficiency

Stoller

Aboussouan

2012

Am J Respir Crit Care Med

389

330

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α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.

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Section: Treatment Of Aatdmentioning

confidence: 99%

A Review of α₁-Antitrypsin Deficiency

Stoller

Aboussouan

2012

Am J Respir Crit Care Med

389

330

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“…The one randomized control trial failed to show significant differences in the rate of decline of FEV 1 or in the rate of loss of lung density, as it was underpowered [161]. The lack of evidence and cost pressures has ultimately limited the use of intravenous α 1 -antitrypsin [162][163][164].…”

Section: Novel Strategies To Treat α 1 -Antitrypsin Deficiency and Thmentioning

confidence: 99%

α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

et al. 2009

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alpha1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes alpha1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant alpha1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (alpha1-antitrypsin and alpha1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of alpha1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.

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“…The main biological role of plasma A1AT is to prevent excessive action of leukocyte-derived Ser proteinases, especially neutrophil elastase, in the circulatory system (Blank and Brantly, 1994). Therapeutic A1AT used in augmentation therapies is currently purified from pooled human serum, and the treatment can cost up to $100,000 per year per patient (Alkins and O'Malley, 2000). Concerns over the supply and safety of the products have urged searches for alternative recombinant sources of A1AT.…”

mentioning

confidence: 99%

Proteolytic andN-Glycan Processing of Humanα1-Antitrypsin Expressed inNicotiana benthamiana

Castilho¹,

Windwarder

Gattinger³

et al. 2014

Plant Physiology

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Plants are increasingly being used as an expression system for complex recombinant proteins. However, our limited knowledge of the intrinsic factors that act along the secretory pathway, which may compromise product integrity, renders process design difficult in some cases. Here, we pursued the recombinant expression of the human protease inhibitor a1-antitrypsin (A1AT) in Nicotiana benthamiana. This serum protein undergoes intensive posttranslational modifications. Unusually high levels of recombinant A1AT were expressed in leaves (up to 6 mg g 21 of leaf material) in two forms: full-length A1AT located in the endoplasmic reticulum displaying inhibitory activity, and secreted A1AT processed in the reactive center loop, thus rendering it unable to interact with target proteinases. We found that the terminal protein processing is most likely a consequence of the intrinsic function of A1AT (i.e. its interaction with proteases [most likely serine proteases] along the secretory pathway). Secreted A1AT carried vacuolar-type paucimannosidic N-glycans generated by the activity of hexosaminidases located in the apoplast/plasma membrane. Notwithstanding, an intensive glycoengineering approach led to secreted A1AT carrying sialylated N-glycan structures largely resembling its serum-derived counterpart. In summary, we elucidate unique insights in plant glycosylation processes and show important aspects of postendoplasmic reticulum protein processing in plants.

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Should Health-Care Systems Pay for Replacement Therapy in Patients With α1-Antitrypsin Deficiency?

Cited by 45 publications

References 22 publications

A Review of α₁-Antitrypsin Deficiency

A Review of α₁-Antitrypsin Deficiency

α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

Proteolytic andN-Glycan Processing of Humanα1-Antitrypsin Expressed inNicotiana benthamiana

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Should Health-Care Systems Pay for Replacement Therapy in Patients With α1-Antitrypsin Deficiency?

Cited by 45 publications

References 22 publications

A Review of α1-Antitrypsin Deficiency

A Review of α1-Antitrypsin Deficiency

α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

Proteolytic andN-Glycan Processing of Humanα1-Antitrypsin Expressed inNicotiana benthamiana

Contact Info

Product

Resources

About

A Review of α₁-Antitrypsin Deficiency

A Review of α₁-Antitrypsin Deficiency