Elucidation of Unfolded Protein Response pathways activated in Lung and Liver Disease associated with Z Alpha-1 Antitrypsin Deficiency

Monday, 24 November 2008 12:41

Health Research Board (HRB)/Medical Research Charities Group (MRCG)

Project Description:

Current treatments for AAT deficiency are based on augmentation therapy with recombinant or plasma-purified AAT and focus almost completely on treating the pulmonary emphysema associated with the disorder. However, the long term efficacy of augmentation therapy has yet to be established, and represents a very expensive therapeutic option. Lung or liver transplantation provides the only effective means of intervention for AAT deficient patients with end-stage lung and liver disease. Unfortunately, while transplantation has been shown to successfully achieve AAT serum conversion, its usefulness as a treatment is confounded by a lack of suitable donors, concomitant immunosuppressive therapy, and high mortality rates. For these reasons it is critically important to develop less invasive therapeutic strategies for the treatment of the lung and liver disease associated with AATD. Conformational diseases are associated with rogue protein accumulation in tissues and cellular compartments. AAT deficiency is one such genetic disease characterised by the accumulation of incorrectly folded AAT in liver cells. The accumulation of mutant Z AAT protein within the cell switches on several protective mechanisms, including the unfolded protein response (UPR). With prolonged activation the UPR becomes harmful to the cell, causes inflammation and ultimately cell death. This is responsible for the cirrhosis observed in the AATD-associated liver disease, but may also be partly responsible for the emphysema seen in AATD-associated lung disease. This may explain why augmentation therapy has yet to be proven clinically effective, and why AAT deficient patients who have received liver transplants still exhibit local inflammation in the lung. We have previously identified intracellular events involved in the molecular pathogenesis of AATD-induced liver disease using an in vitro model system of Z AAT accumulation in liver cells. We will demonstrate that abnormalities in Z AAT-induced liver disease can also be present in Z AAT-induced lung disease. We aim to highlight the crucial involvement of the UPR in Z AAT-associated lung and liver disease. We will show that Z AAT activates the UPR, knocking off protein synthesis, turning on a plethora of UPR-related genes, and activating machinery which degrades the misfolded Z AAT.  We will evaluate the role of UPR mediators in vivo in lung and liver biopsies from individuals with AATD compared to healthy normal individuals.  This discovery-driven project proposal will lead to a greater understanding of AATD, generate several hypotheses, and allow us to identify novel therapeutic avenues for the treatment of AATD-related lung and liver disease.

Duration: 3 years from January 2007


Identification and characterisation of novel pro-inflammatory proteases that excerbate lung disease associated with Z alpha-1 antitrypsin deficiency

Monday, 24 November 2008 12:25

Poster presentations

DA Bergin, Greene CM, Taggart CC, O’Neill SJ and McElvaney NG. Activation of the EGFR by Human Neutrophil Elastase. Royal College of Surgeons in Ireland Research Day, RCSI St. Stephen’s Green, Dublin, April 2006. DA Bergin, CM Greene, CC Taggart, EE Sterchi, SJ O’Neill, NG McElvaney.


Clarification of the Risk of COPD in Alpha-1 antitrypsin (MZ) Individuals

Monday, 24 November 2008 12:20

Funding Body: Alpha-1 Foundation (USA)

Project Description: This clinical research study, to clarify the risk of COPD in MZ individuals, commenced in July 2007 and is supervised by Professor Gerry McElvaney, Department of Medicine RCSI, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.

The purpose of this study is to obtain information about individuals (and their family members) that are carriers of alpha-1 antitrypsin (AAT) deficiency. Acquisition of an abnormal alpha-1 gene from each parent leads to severe deficiency in alpha-1 protein levels which may result in serious lung disease in adults and/or liver disease in infants, children and adults. If an individual inherits an abnormal alpha-1 gene from only one parent, they are a carrier and may be predisposed to developing lung disease. The main objective of this study is to determine whether carriers of alpha-1 antitrypsin deficiency are at an increased risk of developing lung disease. We aim to identify subtle changes in lung function especially in close family members that may allow earlier intervention and treatment. We also aim to investigate whether there are any environmental factors that interact with the abnormal alpha-1 gene that predisposes some but not others to serious lung disease. If identified correctly, such environmental factors may then be avoided thus preventing the development of serious lung disease in carriers of alpha-1 antitrypsin deficiency. Our aim is to enroll 400 parents and siblings of 100 alpha-1 antitrypsin carriers (PiMZ) with diagnosed GOLD Stage 3 or 4 COPD into this study. The inclusion criteria for PiMZ carriers are as follows:

  • Age >30
  • GOLD Stage 3 or 4 COPD (post-bronchodilator FEV1 <50% predicted; FEV1/FVC ratio 0.7)
  • Confirmed PiMZ genotype
  • No other lung diseases that would affect pulmonary function testing (PFT)

The exclusion criteria for relatives of the above PiMZ carriers are as follows:

  • Any interstitial lung diseases
  • Genotypes other than PiMM or PiMZ
  • Non-biological siblings of the PiMZ COPD proband 

Each individual will perform a lung function test (using a portable spirometer), complete a detailed questionnaire (respiratory and liver questions, family history, smoking history etc) and provide blood samples to confirm their carrier status and allow DNA extraction. In the last year, we have recruited 125 individuals into the study from 25 families. Our preliminary results have shown approximately equal numbers of MZ carriers and MM individuals within each family. Our goal is to include as many siblings and parents from each family as possible to participate in this ground-breaking clinical research study. We will determine whether the PiMZ carrier status is associated with an increased risk of COPD and whether cigarette smoking confers an increased risk of COPD in carriers of alpha-1 antitrypsin deficiency. 

If you are an MZ carrier, fulfill the above criteria and are interested in partaking in this clinical research study, please contact:

Dr. Valerie Morris
Respiratory Research Laboratory, Smurfit Building, Beaumont Hospital, Dublin 9.
Tel: +353-1-8093861 or 085-7255506

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Alpha-1 Augmentation Therapy Clinical Trial

Monday, 24 November 2008 12:08

This clinical trial is being conducted in Beaumont Hospital by Professor McElvaney and his team. This is a placebo-controlled, double-blinded, multicentre phase III / IV study to compare the efficacy and safety of the drug Zemaira ® in patients with emphysema due to alpha-1 antitrypsin deficiency. The duration for each patient is 2 years.

We have recruited 16 patients so far and they are all at various stages in the trial. The trial involves having weekly intravenous infusions of Zemaira®, an alpha-1 antitrypsin product or a placebo (which is a mock treatment that looks like the real thing but has none of the activity).

As the study is double-blinded, neither the participating patients nor our study staff knows which therapy has been assigned to them. There is an equal chance of receiving either treatment. As of March 2008 we have had 6 patients graduate onto the extension phase of the study. This is where each patient receives Zemaira for up to another two years. The infusions are given either in Beaumont Hospital or in the patient’s own home and take on average 20 minutes. Every three months patients are required to attend Beaumont Hospital so that routine tests can be carried out. These include: Monitoring of vital signs, i.e. blood pressure, weight etc.

  • Blood tests.
  • Pulmonary Function tests.
  • Physical Examination by physician.
  • Cotinine test (urine test that detects nicotine) is required.

At certain visits a Quality of Life questionnaire and CT scan are performed. These help to investigate the effect of Zemaira® on the development and progression of emphysema within the patients. The main inclusion criteria for all patients that enter onto the study are: · Diagnosis of alpha-1 antitrypsin deficiency (ZZ phenotype).

  • Non smokers or Ex-Smokers who have stopped at least 6 months prior to screening.
  • Age range of 18 – 65 years of age, male and female.
  • Emphysema with an FEV1 of 35-70% predicted range.

As with other alpha-1 therapies, Zemaira® may not be appropriate for the following adults:

  • Individuals with a known hypersensitivity and/or history of anaphylaxis or severe systemic reaction to alpha-1 antitrypsin products or their components.
  • Individuals with selective IgA deficiencies who have known antibodies against IgA. This is due to Zemaira® being derived from human plasma.

All patients however will be assessed on an individual basis. In previous clinical studies, Zemaira® has been shown to be generally well tolerated and provides patients with half or less the infusion time of other available alpha-1 augmentation therapies. If you would like any further information on Zemaira® or you are interested in taking part in the trial please feel free to contact:

Máire Stack
Tel: 01 8093864/01 8093876
Research Nurse, Study Co-Ordinator

What is Alpha-1 Antitrypsin?
Alpha-1 antitrypsin is a vital protein produced by the liver to protect the lungs. It provides protection from the harmful effects of infections and inhaled irritants, particularly tobacco smoke. It can be easily measured by a simple blood test. 
What is Alpha-1 Antitrypsin Deficiency?
Alpha-1 antitrypsin deficiency (Alpha-1) is a genetic condition which, after cystic fibrosis, is the commonest genetic disorder in Ireland. It severely affects more than 15,000 people, with another 250,000 carriers also at risk of lung and liver disease on the island of Ireland. It is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD).
How Do I Get Tested?
The Alpha One Foundation provides free testing for Alpha-1 as part of a national screening programme which is funded by the HSE. For more details ring 01-8093871 or email alpha1@rcsi.ie.