Article
Respiratory System
Alexa Nunez, Irene Belmonte, Elena Miranda, Miriam Barrecheguren, Georgina Farago, Eduardo Loeb, Monica Pons, Francisco Rodriguez-Frias, Pablo Gabriel-Medina, Esther Rodriguez, Joan Genesca, Marc Miravitlles, Cristina Esquinas
Summary: This study investigated the association between levels of CP of AAT with severity of lung and liver disease in AATD patients. Pi*ZZ patients had the highest CP concentrations, especially those with impaired lung function and increased liver stiffness. These findings suggest that CP may be helpful in identifying patients at higher risk of developing lung and liver disease.
RESPIRATORY RESEARCH
(2021)
Article
Medicine, Research & Experimental
Nan He, Xiaoming Liu, Amber R. Vegter, T. Idil A. Evans, Jaimie S. Gray, Junfeng Guo, Shashanna R. Moll, Lydia J. Guo, Meihui Luo, Ningxia Ma, Xingshen Sun, Bo Liang, Ziying Yan, Zehua Feng, Lisi Qi, Arnav S. Joshi, Weam Shahin, Yaling Yi, Katherine N. Gibson-Corley, Eric A. Hoffman, Kai Wang, Christian Mueller, John F. Engelhardt, Bradley H. Rosen
Summary: Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease. This study used ferret models to demonstrate that complete loss of AAT and the most common mutation in AAT result in lung and hepatic diseases similar to those observed in AATD patients, making them a potential platform for preclinical testing of therapeutics including gene therapy.
Article
Gastroenterology & Hepatology
Christoph Grander, Benedikt Schaefer, Julian Schwaerzler, Felix Grabherr, Dennis M. de Graaf, Barbara Enrich, Georg Oberhuber, Lisa Mayr, Moris Sangineto, Nikolai Jaschke, Timon E. Adolph, Maria Effenberger, Alexander R. Moschen, Charles A. Dinarello, Heinz Zoller, Herbert Tilg
Summary: ALD is a global healthcare issue with limited treatment options. AAT has shown potent anti-inflammatory activities and low serum concentrations are associated with increased risk of death/liver transplantation in cirrhotic ALD patients. Experimental models in mice suggest that AAT may be a potential therapeutic option for ALD, especially for alcoholic hepatitis.
Article
Medicine, Research & Experimental
David A. Lomas, James A. Irving, Christopher Arico-Muendel, Svetlana Belyanskaya, Andrew Brewster, Murray Brown, Chun-wa Chung, Hitesh Dave, Alexis Denis, Nerina Dodic, Anthony Dossang, Peter Eddershaw, Diana Klimaszewska, Imran Haq, Duncan S. Holmes, Jonathan P. Hutchinson, Alistair M. Jagger, Toral Jakhria, Emilie Jigorel, John Liddle, Ken Lind, Stefan J. Marciniak, Jeff Messer, Margaret Neu, Allison Olszewski, Adriana Ordonez, Riccardo Ronzoni, James Rowedder, Martin Ruediger, Steve Skinner, Kathrine J. Smith, Rebecca Terry, Lionel Trottet, Iain Uings, Steve Wilson, Zhengrong Zhu, Andrew C. Pearce
Summary: The study identified small molecules that bind to and stabilize mutant alpha(1)-antitrypsin, blocking aberrant polymerisation and increasing secretion, providing a potential treatment for deficiency. Oral dosing in transgenic mice showed a significant increase in secretion without observable clearance of hepatic inclusions, demonstrating the potential of mutation ameliorating small molecules in treating the disease.
EMBO MOLECULAR MEDICINE
(2021)
Article
Cardiac & Cardiovascular Systems
Dimitrios Toumpanakis, Omar S. Usmani
Summary: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that leads to panacinar emphysema and increases the risk of chronic obstructive pulmonary disease (COPD), especially in smokers. AATD is caused by mutations in the SERPINA1 gene, which affects the production of alpha-1 antitrypsin (AAT) protein. AAT not only acts as a protease inhibitor, but also has anti-inflammatory and antioxidative effects. Imbalance in protease/antiprotease levels not only affects the lung parenchyma, but also the small airways.
RESPIRATORY MEDICINE
(2023)
Article
Medicine, General & Internal
K. A. Serban, K. A. Pratte, C. Strange, R. A. Sandhaus, A. M. Turner, T. Beiko, D. A. Spittle, L. Maier, N. Hamzeh, E. K. Silverman, B. D. Hobbs, C. P. Hersh, D. L. DeMeo, M. H. Cho, R. P. Bowler
Summary: This study identified unique and shared plasma biomarkers between AATD and COPD subjects, and generated a protein score strongly associated with emphysema. Unique biomarkers associated with DLCO and emphysema were found in PiZZ AATD patients.
Article
Biochemistry & Molecular Biology
Noor Ahmad Shaik, Najla Bint Saud Al-Saud, Thamer Abdulhamid Aljuhani, Kaiser Jamil, Huda Alnuman, Deema Aljeaid, Nasreen Sultana, Ashraf AbdulRahman El-Harouni, Zuhier Ahmed Awan, Ramu Elango, Babajan Banaganapalli
Summary: This study investigates the impact of SERPINA1 missense variants on the structural and functional characteristics of A1AT protein in Alpha-1 antitrypsin deficiency. The results suggest that these variants alter the structure, stability, and function of A1AT protein, and negatively affect its binding with NE ligand molecule.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Pharmacology & Pharmacy
Vickram Tejwani, James K. Stoller
Summary: AAT deficiency predisposes individuals to lung, liver, skin, and vascular diseases. Timely diagnosis and intervention are crucial for slowing the progression of emphysema. AAT augmentation therapy is currently the only known effective treatment for reducing the progression of emphysema.
THERAPEUTIC ADVANCES IN CHRONIC DISEASE
(2021)
Article
Genetics & Heredity
Robert Stockley, Anita Pye, Joshua De Soyza, Alice F. Turner, Marc Miravitlles, EARCO Study Investigators
Summary: This study found that 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency have bronchiectasis alone, and 27% of emphysema patients also have bronchiectasis. This indicates that although emphysema is the predominant lung pathology, bronchiectasis may require a different treatment strategy.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Zuzana Rabekova, Sona Frankova, Milan Jirsa, Magdalena Neroldova, Mariia Lunova, Ondrej Fabian, Martin Kveton, David Varys, Klara Chmelova, Vera Adamkova, Jaroslav A. Hubacek, Julius Spicak, Dusan Merta, Jan Sperl
Summary: The study found that patients with liver cirrhosis carrying the SERPINA1 MZ and MS genotypes have a significantly lower risk of hepatocellular carcinoma. MZ and MS heterozygotes have lower serum AAT levels. Multivariate analysis identified MZ or MS genotype carriage as a protective factor, while factors such as age, gender, BMI, and viral aetiology of cirrhosis increase the risk of HCC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Dhiren Patel, Jeffrey Teckman
Summary: Alpha-1 antitrypsin deficiency (AATD) liver disease is the second leading cause of death among patients with the condition, primarily due to diverse manifestations of liver disease caused by AAT aggregates within hepatocytes. Although there is currently no licensed treatment for AATD-related liver disease, liver transplantation may yield positive outcomes.
THERAPEUTIC ADVANCES IN CHRONIC DISEASE
(2021)
Article
Medicine, General & Internal
Anna Annunziata, Ilaria Ferrarotti, Antonietta Coppola, Maurizia Lanza, Pasquale Imitazione, Sara Spinelli, Pierpaolo Di Micco, Giuseppe Fiorentino
Summary: The study evaluated the incidence of alpha-1 antitrypsin deficiency in patients with chronic pulmonary disease in Naples, Italy. Results showed 36 patients with intermediate AAT levels deficiency, with rare variants and compound heterozygosity. The study supports early diagnosis and treatment for patients with chronic pulmonary disease.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Nazli Khodayari, Rejean L. Wang, Regina Oshins, Yuanqing Lu, Michael Millett, Alek M. Aranyos, Sayedamin Mostofizadeh, Yogesh Scindia, Tammy O. Flagg, Mark Brantly
Summary: Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the SERPINA1 gene, leading to the accumulation of misfolded alpha-1 antitrypsin (ZAAT) in hepatocytes, which is associated with mitochondrial dysfunction. Research has shown that ZAAT aggregation in hepatocytes results in abnormal mitochondrial morphology and function, disrupting lipid metabolism balance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Daniella A. Spittle, Alison Mansfield, Anita Pye, Alice M. Turner, Michael Newnham
Summary: The progression of lung disease in alpha-1 antitrypsin deficiency (AATD) varies and presents differently. Blood biomarkers are a convenient and repeatable method of monitoring diseases. In this study, we compared the levels of seven serum biomarkers between AATD patients with and without COPD. We found that CRP and CCL18 were significantly higher in AATD COPD patients. CC16 was found to be predictive of emphysema progression in AATD COPD.
Review
Pharmacology & Pharmacy
Yuh-Chin Tony Huang, Marion Wencker, Bastiaan Driehuys
Summary: Imaging modalities such as CT play a crucial role in assessing COPD patients, especially those with AATD, providing essential diagnostic and treatment information. MRI is emerging as a promising complement to CT, offering comprehensive measures of lung function without the radiation associated with CT.
THERAPEUTIC ADVANCES IN CHRONIC DISEASE
(2021)