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AAT Deficiency (AATD): Pursuing the Cure for the “Alphas”

By: , Posted on: September 6, 2017

Alpha-1 antitrypsin (AAT) is a protein produced by the liver with remarkable anti-inflammatory properties. AAT deficiency (AATD) is a hereditary condition that mainly affects Caucasians (Whites) of European heritage, although occasionally it can also affect individuals of other races (https://www.alpha1.org/Newly-Diagnosed/More-Alpha-1-Resources/Alpha-Stories/ArtMID/3897/ArticleID/6219). Individuals with AATD (colloquially referred to as “Alphas”) usually have a genotype called PiZ. In 65 of the 193 countries in the world with reliable data, there are at least 250,000 “Alphas” with severe AATD, most European, American, Australian and New Zealanders Caucasians (Figure 1).

Figure 1

Without being exhaustive, it can be said that severe AATD predisposes to chronic hepatitis and liver cirrhosis in children and adults, and early-onset of chronic obstructive pulmonary disease (COPD) in adults (typically pulmonary emphysema in cigarette smokers). Much less frequently, AATD is associated with systemic vasculitis type Wegener’s granulomatosis, neutrophilic panniculitis, and to other inflammatory, autoimmune and neoplastic diseases (Figure 2)

Figure 2

AATD is underdiagnosed. In practice, more than half of “Alphas” may have COPD and / or liver cirrhosis, erroneously attributed to tobacco or alcohol without being tested for AATD; a minority may suffer from vasculitis, panniculitis, or several diseases at once; and approximately one third are asymptomatic but at high risk of developing diseases, which could be prevented with an early diagnosis.

This congenital condition is characterized by the production of a defective protein (called Z protein) that forms stable polymers which are retained within hepatocytes in which they trigger cellular stress that can cause liver damage. Secondarily, the retention of mutated proteins in the liver leads to a decreased concentration and activity of AAT in blood and tissues, which are deprived of anti-inflammatory protection (Figure 2).

Augmentation therapy with intravenous periodic infusions of purified plasma-derived AAT for lung-affected AATD individuals is currently available in several developed countries. In addition, the recently discovered potent anti-inflammatory, anti-apoptotic, and immunomodulatory properties of the AAT have attracted the interest of researchers for assessing its potential use in different diseases, either related or unrelated to AATD, which has led to a singular increase in patents and clinical trials. On the contrary, since the AATD-associated liver disease is due to the retention of mutant Z protein into the hepatocytes, the only available treatment for advanced cirrhosis is liver transplantation. Nevertheless, to make up for this lack of therapeutic resources, in latest years there has been a remarkable scientific activity aimed at developing new therapeutic strategies for AATD, including liver polymers formation blockage, liver autophagy enhancing drugs, and several modalities of “cellular” and gene therapy with the final objective of obtaining the cure for the “Alphas”.

For a limited time, you can download a free chapter on “Genetic Epidemiology” from Blanco’s Overview of Alpha-1 Antitrypsin Deficiency.

Want it in print? Save up to 30% off by using STC317 at Elsevier.com

 

 

 

About the Author:

Ignacio Blanco (Grado, Asturias, Spain, 1944) is a MD graduated at the Medical School of the University of Valladolid, Spain, in 1968.

Specialist in Internal Medicine and Pulmonology.

Since 1993-currently he collaborates as an advisor or coordinator for the Spanish Registry of Alpha-1 Antitrypsin Deficiency (AATD), being his career activity mainly focused on AATD research.

Among the works that he has published in both Spanish and international impact journals, over 50 of them are related to different aspects of the AATD. He has coordinated the first book in Spanish on AATD, published by the Spanish Society of Pulmonology (SEPAR) in 2012, and has also coordinated in 2016 the second edition of this book for Spanish-speaking pulmonologists. In 2014, he participated in the publication of the Spanish Guide to Alfa patients, published by SEPAR.

From 2007-2010, he took part in the special Programme for the Intensification of the Research Activity of the Spain’s Institute of Health Carlos III.

He is inventor of the International patent “Use of Alpha-1 Antitrypsin for the preparation of medicaments for the treatment of fibromyalgia” [(Prior Publication US 2006/0084598 A1, Apr. 20, 2006 Int. Cl. A61K 38/17 (2006.01); C12N 9/76 (2006.01)]

Dr.Blanco has been listed in the 2011 edition of Who’s Who in Medicine and Healthcare from The U.S.

Since 2008-currently, he is evaluator of research projects for the National Agency for Assessment and Forecasting (ANEP), a unit which is dependent on the Secretary of State for Research, of the Ministry for Science and Innovation.

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