Alpha-1 Antitrypsin Deficiency

Researchers Clinicians

If I have seen further it is by standing on ye sholders of Giants

Isaac Newton 1676

personal views from . . .

Dr. Bruno Balbi

Presidente  Comitato Scientifico Associazione Nazionale Alfa1-AT Onlus ITALIA

Carissimi Alfa,
50 anni sono tanti eppure l’alfa-1 non li dimostra! Dal 1963 ad oggi infatti sono stati fatti molti progressi nel nostro (vostro?) campo. Il meccanismo che genera l’enfisema (mancanza di alfa-1) e quello che genera l’epatopatia (accumulo di alfa-1) è stato messo in luce. Il gene dell’alfa-1 e le sue mutazioni sono ormai conosciute. La “cura” dell’enisema da alfa1 è stata sperimentata, approvata e utilizzata su larga (larghissima!) scala cone evidenti effetti positivi. Oltre a ciò, a partire dagli USA ma ormai da molti anni anche nel resto del mondo, i pazienti alfa-1 sono un modello per l’associazionismo tra pazienti. Fund-rising, patient empowerment, stake-holders partnership, screening sono tutte parole che anche in Italia sono diventate patrimonio degli Alfa, raggruppati dal 2001 nella Associazione Nazionale Alfa1-AT di cui mi onoro di essere, assieme ad altri, Socio Fondatore.  Celebriamo quindi i nostri “primi” 50 anni con soddisfazione ma anche con rinnovato impegno. Un impegno che deriva dalla consapevolezza sia dei traguardi raggiunti che di quelli ancora da raggiungere. Buon 50enario a tutti gli Alfa!

Professor David Lomas  PhD ScD FRCP FMedSci

Dean of the Faculty of Medical Sciences and Chair of Medicine UCL (elect)

I have undertaken research on antitrypsin deficiency for 22 years.  It is my aim to develop small molecules that offer a cure for this condition.

  • Profile

    Professor Lomas runs programmes at the University of Cambridge for developing clinical and basic scientists, including the Wellcome Trust PhD programme for clinicians, and a 4 year basic science PhD programme in the Cambridge Institute for Medical Research. He is Chair of the Population and Systems Medicines Board at the MRC, the Grants Advisory Committee of the Alpha-1 Foundation in Amaerica, the GSK Respiratory Therapy Area Board and the Research Committee of the British Lung Foundation, where he is also a Trustee. His research interests are focused on the pathobiology of α1-antitrypsin deficiency, the serpinopathies and COPD.


Professor Sabina Janciauskiene

Medizinische Hochschule Hannover, Germany

Half century clearly shows the changes in science of Alpha-1 antitrypsin

When I think about Alpha1, I always imagine sea in Malmö when I have started to search for different functions of alpha1 – broad like search for horizons of the sea. Now I am older, and I feel like I am in the forest searching for specific little connections – for the mechanism of Alpha1 action. In fact, I am in Hannover – city of forest.

All research in Alpha1 turned to the direction of the mechanism. Understanding of Alpha1 function will ultimatelyhelp protect us not only from emphysema but from many serious diseases.

  • Profile

    Sabina Janciauskiene has obtained doctor degrees in Pharmacy, Biology, Immunology and Experimental medicine. For 20 years the overall objective of her research has been to investigate the mechanisms that control inflammation, with particular emphasis on the multiple roles of serine protease inhibitors (serpins) in Alzheimer‘s disease and chronic obstructive pulmonary disease. As an acknowledgement of her research achievements, she received the European CB Laurell Award 2005 for new insights into Alpha1-antitrypsin deficiency.


Professor Robert A Stockley MD DSc FRCP

BBC CLRN Clinical Director

A long way to go but the field now contains many more clinicians and researchers who have taken up the challenge that requires this unique blend of science and clinical research so that  together with strong patient support and advocacy we can make it.

  • My story

    Following the original recognition of the association between alpha-1-antitrypsin deficiency (AATD) and early onset, predominantly basal emphysema a simplified concept of the pathophysiology of the disease, and hence its treatment emerged.  AAT is a key inhibitor of enzymes especially those from the neutrophil and studies in experimental models confirmed that such enzymes could induce emphysema in animals.  The data was extrapolated to man leading to the proteases/antiprotease hypothesis that neutrophil enzymes could cause emphysema and in subjects with AATD the lack or low level of AAT was insufficient to protect the lungs from these enzymes and hence the emphysema process.  The next logical step was therefore to restore the AAT and all would be well.  Indeed in the early 1980s it was announced by US workers that “AAT was discovered in the 60s and cured in the 80s”.

    The logic behind this was so strong that many countries adopted augmentation therapy as a treatment without conventional clinical trials of efficacy.  Nevertheless some countries (notably the UK, Denmark, Sweden and Holland) have so far failed to accept this logic and hence have not awarded a license and/or reimbursement for this therapy in patients with emphysema.

    My own interest in AATD started in the late 70s with both clinical and biochemical studies of AAT and its’ deficiency.  However it become clear that the story was far from simple and in collaboration with a local colleague in Hereford who used to measure AAT in everyone.I became aware that the presence of AATD did not necessarily mean the development of lung disease even in smokers.  Nevertheless the general acceptance of the logical concept of the process of emphysema development resulted in little support for further research funding in AATD.

    However in the 90s things changed.  David Lomas was my registrar who challenged me to undertake such bench work again to see if I was “up to it”.  Fortunately, I passed the test and he and I discussed the nature and role of AAT with renewed vigour until he “abandoned” me to take up his successful research career in Cambridge.

    By the mid 1990s I was approached by Bayer Biologicals to explain why augmentation was not available in the UK.  My reply was “because there is no proof of clinical efficacy provided by a proper clinical trial”.  The next question was “could you do such a trial?” and my answer was “No. Because no-one understands the disease and its’ progression and effect on patient’s well enough to design a trial that has meaning to the patients and doctors in the short and long term”.  This began the long and fruitful collaboration that established ADAPT (Antitrypsin Deficiency and Programme for Treatment.

    The collaboration  has been highly successful in learning about the clinical variations of what was believed to be a single disease process, the role of other genetic modifiers, the variability in lung function decline, the role of exacerbations, the validation of CT scanning as the most sensitive outcome measure in AATD and hence the design and delivery of clinical trials of augmentation therapy, new strategies in gene correction and even studies on the liver (some of these publications are listed below). This unique combination of basic science and clinical observation leading to understanding of the disease and the design of clinical trials has been central to where we are today.  This has been supported by the establishment of AIR (the Alpha-1 International Registry) to facilitate collaborative  research between countries  that resulted in 3 successful European Union Framework grants and the delivery of 3 major clinical trials.

    The wealth of information generated (particularly related to the natural history of AATD) together with the EXACTLE trial now places us in a good position to make a case for national commissioning of an NHS AATD service and treatment despite some continued scepticism about the efficacy of augmentation from some quarters.  We know that not all AATD subjects require augmentation as many stabilise once they stop smoking.  However undoubtedly others do and augmentation should slow or stop this progression.  Our challenges thus remain:- who needs augmentation and when; how should they receive it (injected or inhaled); do they need it all the time (or just for chest infections); how do we predict individuals who will progress before they do so that we can intervene earlier and how do we design trials for new therapies such as small molecules, oral anti-elastase drugs  and gene therapy.

    • A selection of some of the references that have lead us to where we are today

      R. A. Stockley (1979).  Alpha1-antitrypsin phenotypes in cor pulmonale due to chronic obstructive airways disease.  Quart. J. Med.; 191: 419-428.

      D. Burnett and R. A. Stockley (1980).  The electrophoretic mobility of alpha1-antitrypsin in sputum and its relationship to protease inhibitory capacity, leucocyte elastase concentrations and acute respiratory infection.  Hoppe-Seylers Z. Physiol. Chem; 361: 781-789.

      R. A. Stockley, S. C. Afford and D. Burnett (1982). The electrophoretic mobility of alpha1-proteinase inhibitor: effects of proteolysis and cigarette smoking.  Hoppe-Seylers Z. Physiol. Chem; 365: 387-393.

      A. B. M. G. Mostafa, N. J. Tulley, L. K. Harding and R. A. Stockley (1983).  Regional distribution of ventilation and perfusion in patients with obstructive pulmonary disease and alpha1-antitrypsin deficiency.  Eur. J. Nucl. Med., 8: 338-341.

      H. M. Morrison, D. Burnett and R. A. Stockley (1986).  The effect of reducing agents on proteolytic enzymes and oxidation of alpha1-proteinase inhibitor.  Biol. Chem. Hoppe-Seyler; 367: 177-182.

      H. M. Morrison, D. Burnett and R. A. Stockley (1986).  The effect of catalase and methionine sulfoxide peptide reductase on oxidised alpha1-proteinase inhibitor.  Biol. Chem. Hoppe-Seyler; 367: 371-378.

      H. M. Morrison, H. G. Welgus, R. A. Stockley, D. Burnett and E. J. Campbell (1990).  Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity.  Am. J. Respir. Cell Mol. Biol; 2: 263-269

      A. T. Hill, E. J. Campbell, D. L. Bayley, S. L. Hill and R. A. Stockley (1999).  Evidence for excessive bronchial inflammation during an acute exacerbation of COPD in patients with alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med, 160: 1968-1975

      L.J.Dowson, P.J.Guest and R.A.Stockley (2001). Longitudinal changes in physiological, radiological, and health status measurements in a1-antitrypsin deficiency and factors associated with decline.  Am J Respir Crit Care Med; 164: 1805-1809.

      L.J. Dowson, P. J. Guest, S.L. Hill, R.L. Holder and  R.A. Stockley (2001).  High-resolution computed tomography scanning in α1-antitrypsin deficiency: relationship to lung function and health status.  Eur Respir J; 17: 1097-1104.

      L.J.Dowson, P.J.Guest and R.A.Stockley (2002). The relationship of chronic sputum expectoration to physiologic, radiologic, and health status characteristics in 1-antitrypsin deficiency (PiZ). Chest; 122: 1247-1255.

      P.A.Dawkins, L.J.Dowson, P.J.Guest, R.A.Stockley (2003). Predictors of mortality in 1-antitrypsin deficiency. Thorax; 58: 1020-1026

      D. G. Parr, B. C. Stoel, J. Stolk, R. A. Stockley (2004) Pattern of emphysema distribution in α-1-antitrypsin deficiency influences lung function impairment. American Journal of Respiratory Critical Care Medicine, 170 (11): 1172-1178

      M Needham and R.A.Stockley (2005). Exacerbations in α-1-antitrypsin deficiency. Eur Respir J; 25: 992-1000.

      D. G. Parr, B. C. Stoel, J. Stolk, R. A. Stockley (2006) Validation of computed tomographic lung densitometry for monitoring emphysema in α-1-antitrypsin deficiency. Thorax, 61; 485-490.

      J. Holme and R.A.Stockley (2007). Radiologic and clinical features of COPD patients with discordant pulmonary physiology: Lessons from a-1-antitrypsin deficiency. Chest; 132: 909-915

      G. L. McNab, A. Ahmad, D. Mistry, R. A. Stockley (2007) Modification of gene expression and increase in α1-antitrypsin (α1-AT) secretion after homologous recombination in α1-AT-deficient monocytes. Human Gene Therapy, 18: 1171-1177.

      A.M.Wood, R.M.Harrison, S.Semple, J.G.Ayres, R.A.Stockley (2009)  Outdoor air pollution is associated with disease severity in a1-antitrypsin deficiency. Eur Respir J, 34: 346-353

      J.Holme, P.A.Dawkins, E.K.Stockley, D.G.Parr, R.A.Stockley (2010) Studies of gamma-glutamyl 1 transferase in alpha-1 antitrypsin deficiency. COPD, 7 (20): 126-32

      E.Sapey, A.M.Wood, A.Ahmad, R.A.Stockley (2010) TNFalpha rs361525 polymorphism is associated with increased local production and downstream inflammation in COPD. Am J Respir Crit Care Med, 15;182(2):192-9

      A.M. Wood, R.M. Harrison, S. Semple, J.G. Ayres, R.A. Stockley (2010) Outdoor air pollution is associated with rapid decline of lung function in alpha-1-antitrypsin deficiency. Occup Environ  Health;67 (8): 556-61.

      R.A.Stockley, D.G.Parr, E.Piitulainen, J.Stolk, B.C.Stoel, A.Dirksen (2010) Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry Respir Res, 11: 136

      G.L.MacNab, T.R.Dafforn, A.Wood, E.Sapey, R.A.Stockley (2012) A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency. Mamm Genome; 23: 241-249. DOI 10.1007/s00335-011-9370-2