Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial

Chapman, Kenneth R.; Burdon, Jonathan; Piitulainen, Eeva; Sandhaus, Robert A.; Seersholm, Niels; Stocks, James M.; Stoel, Berend C.; Huang, Liping; Yao, Zhenling; Edelman, Jonathan M.; McElvaney, Noel G.

doi:10.1016/s0140-6736(15)60860-1

Cited by 440 publications

(448 citation statements)

References 23 publications

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“…Moreover, the relevance of decline in forced expiratory volume in 1 s (FEV 1 ) as an endpoint in respiratory disease is increasingly debated given recent data highlighting a developmental cause for reduced lung function [65]. The RAPID investigators have recently reported a 24 month study in which 93 individuals were randomised to active therapy and 87 to received placebo [66]. The annual rate of lung density loss at total lung capacity (TLC) and functional residual capacity (FRC) combined did not differ between groups.…”

Section: Treatment For Lung Disease Associated With α 1 -Antitrypsin mentioning

confidence: 99%

Update on alpha-1 antitrypsin deficiency: New therapies

Lomas

Hurst

Gooptu

2016

Journal of Hepatology

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α 1 -antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α 1 -antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α 1 -antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α 1 -antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α 1 -antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies.The detailed understanding of the pathobiology of α 1 -antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials.We provide an overview of these new therapies for the liver and lung disease associated with α 1 -antitrypsin deficiency.

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Section: Treatment For Lung Disease Associated With α 1 -Antitrypsin mentioning

confidence: 99%

Update on alpha-1 antitrypsin deficiency: New therapies

Lomas

Hurst

Gooptu

2016

Journal of Hepatology

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“…administration of AAT in AATD has been shown to be safe and well tolerated (36,37) and results in increased levels of AAT in bronchoalveolar lavage fluid (38), a slower rate of forced expiratory volume in 1 s (FEV 1 ) decline (39), and reduced loss of lung tissue (40). The recent RAPID study, which was a multicenter, placebo-controlled trial of AAT treatment, demonstrated that the annual rate of lung density loss at total lung capacity was significantly less in patients receiving therapy (p = 0·03) (41). However, despite the observed clinical effects of AAT, further proof of the mechanism of action of augmentation therapy is required (42).…”

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confidence: 99%

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

O’Dwyer

O’Brien

Wormald

et al. 2015

The Journal of Immunology

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Leukotriene B4 (LTB4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB4-related disease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB4 inflammatory cycle in AATD, causing increased LTB4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB4. We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and downstream signaling events, including 1,4,5-triphosphate production and Ca2+ flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB4-related diseases.

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“…Even though the FDA approval was granted on the basis of the logic of biochemical efficacy, no clinical efficacy was demonstrated at the time. In a recent 2-year multicenter, double-blind, randomized, placebo-controlled trial (the RAPID trial) Chapman and colleagues (78) provided evidence that the therapy slows the progression of lung destruction, measured by computer tomography lung density at total lung capacity as the primary outcome.…”

Section: Aat Augmentation Therapy With Human Aat Purified From Pooledmentioning

confidence: 99%

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

Chiuchiolo

Crystal

2016

Annals ATS

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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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Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial

Cited by 440 publications

References 23 publications

Update on alpha-1 antitrypsin deficiency: New therapies

Update on alpha-1 antitrypsin deficiency: New therapies

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

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