Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence

Brantly, Mark; Lascano, Jorge; Shahmohammadi, Abbas

doi:10.15326/jcopdf.6.1.2017.0185

Cited by 22 publications

(41 citation statements)

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“…Variable mutations in the A1AT gene cause deficiency of functional protein, resulting in proteolytic lung damage and panlobular emphysema (18). Augmentation treatment of A1AT has been approved for the treatment of A1AT deficiency (19).…”

Section: Previously A1at Was Shown To Inhibit the Infection Of H3n2 mentioning

confidence: 99%

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Azouz

Klingler

Callahan

et al. 2020

Preprint

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The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-CoV, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an approach toward preventing transmission of coronaviruses. Herein, we developed an in vitro system to measure TMPRSS2 activity and tested the inhibition of TMPRSS2 by several synthetic and natural protease inhibitors. Camostat mesylate and bromhexine hydrochloride (BHH) inhibited TMPRSS2 proteolytic function. In addition, we identified the small molecule 4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF) and the human, anti-inflammatory protein alpha 1 antitrypsin (A1AT) as inhibitors of TMPRSS2. AEBSF and A1AT inhibited TMPRSS2 activity in a dose-dependent manner. AEBSF and A1AT inhibited TMPRSS2 in the same range of concentrations (100-0.1 μM). We suggest that treatment with these inhibitors, particularly A1AT, which is an FDA-approved drug, might be effective in limiting SARS-CoV and SARS-CoV2 transmissibility and as a COVID-19 treatment.

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Section: Previously A1at Was Shown To Inhibit the Infection Of H3n2 mentioning

confidence: 99%

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Azouz

Klingler

Callahan

et al. 2020

Preprint

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“…Other studies published since 2010 have investigated the clinical efficacy of AAT therapy [40]. In particular, the RAPID-RCT/RAPID Extension (RAPID-OLE) trial [41,42] is the largest randomised, placebo-controlled trial of AAT therapy completed to date.…”

Section: Best Practice In Diagnosis Of Pulmonary Diseases In Aatdmentioning

confidence: 99%

“…With regard to the correct dosing interval, only the 60 mg·kg −1 weekly dose has been shown to consistently maintain AAT serum levels above the 11 μM (57 mg·dL −1 ) threshold, whereas serum AAT levels have been shown to decrease below 11 μM 1-2 days prior to the next dose with 120 mg·kg −1 every 2 weeks [40]. Longer dosing intervals may be beneficial in certain situations, e.g.…”

Section: Lung Transplantationmentioning

confidence: 99%

“…In any case, areas for future research include also the need to identify an average terminal lung density threshold in AATD and emphysema to help quantify treatment advantage with AAT therapy [40]. Efforts should focus on identifying the optimal dosage/dosage interval and further study is required to confirm efficacy of AAT therapy in both early-and late-stage disease suggested by the RAPID-RCT data.…”

Section: Ongoing Research and Future Treatmentsmentioning

confidence: 99%

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α₁-Antitrypsin deficiency and chronic respiratory disorders

et al. 2020

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α1-antitrypsin deficiency (AATD) is a hereditary disorder associated with a risk of developing liver disease and pulmonary emphysema, and other chronic respiratory disorders (mainly asthma and bronchiectasis); Z variant is the commonest deficient variant of AAT. Determining AAT concentration in serum or plasma and identifying allelic variants by phenotyping or genotyping are fundamental in the diagnosis of AATD. Initial evaluation and annual follow-up measurement of lung function, including post-bronchodilator forced expiratory volume in 1 s and gas transfer inform on disease progression. Lung densitometry is the most sensitive measure of emphysema progression, but must not be use in the follow-up of patients in routine clinical practice. The exogenous administration of purified human serum-derived AAT is the only approved specific treatment for AATD in PiZZ. AAT augmentation therapy is not recommended in PiSZ, PiMZ or current smokers of any protein phenotype, or in patients with hepatic disease. Lung volume reduction and endoscopic bronchial valve placement are useful in selected patients, whereas the survival benefit of lung transplant is unclear. There are several new lines of research in AATD to improve the diagnosis and evaluation of the response to therapy and to develop genetic and regenerative therapies and other treatments.

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“…However, an in-vitro quantum proteolysis study did support the validity of a threshold of approximately 11 µM (≈57.2 mg/dL), as a non-linear relationship was found between AAT concentration and the magnitude of quantum proteolytic events, with a dramatic increase observed at AAT concentrations below ~11 µM (≈57.2 mg/dL) [35]. Furthermore, utilising this threshold as a guide and raising AAT levels above this level with intravenous AAT therapy has been shown to be clinically effective in PI*ZZ individuals [36].…”

Section: Research Questionmentioning

confidence: 95%

Clinical considerations in individuals with α₁-antitrypsin PI*SZ genotype

et al. 2020

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α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM “protective threshold” for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

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Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence

Abstract: For personal use only. Permission required for all other uses.

Cited by 22 publications

References 56 publications

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

α₁-Antitrypsin deficiency and chronic respiratory disorders

Clinical considerations in individuals with α₁-antitrypsin PI*SZ genotype

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Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence

Abstract: For personal use only. Permission required for all other uses.

Cited by 22 publications

References 56 publications

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

α1-Antitrypsin deficiency and chronic respiratory disorders

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype

Contact Info

Product

Resources

About

α₁-Antitrypsin deficiency and chronic respiratory disorders

Clinical considerations in individuals with α₁-antitrypsin PI*SZ genotype