Research Funded (2016-2017)
Chronic obstructive pulmonary disease (COPD) →
Lung Disease →
Lung Infection →
Lung Transplantation →
Mechanical Ventilation →
Other Areas of Lung Research →
Dr. Diane Lougheed, Queen’s University
Validation of the Work-related Asthma Screening Questionnaire – Long Version (WRASQ(L))
It is estimated that work-related asthma (WRA) accounts for approximately 20% of all adult asthma. Ongoing workplace exposure after the onset of symptoms has been shown to contribute to poor outcomes. Early detection of WRA leads to better management, which may reduce health-care costs due to missed work and reduce income loss. Yet, the diagnosis of WRA is often delayed or overlooked, at least in part due to lack of awareness of the potential causes of WRA and challenges health-care providers face finding time to take a history of workplace exposures. Currently, there is no validated tool or questionnaire for use in clinical practice to promote early detection or identification of WRA.
We recently developed a WRA screening questionnaire designed to identify possible WRA, and prompt both appropriate additional testing and/or referral a specialist to verify the diagnosis, as well as preventive strategies in individuals without current WRA symptoms who are at high risk due to their workplace exposures. However, this questionnaire needs to be validated before it is broadly implemented in clinical practice. The purpose of this research is to evaluate the ability of a work-related asthma screening questionnaire to reliably detect individuals whose asthma is likely caused or worsened by workplace exposures.
The findings will provide evidence to guide decisions about the merit of integrating this into practice. This study is the first step of part of a large team grant in which we propose to compare the direct and indirect costs of WRA compared to non-WRA, and to measure the health and economic benefit of early detection of WRA in clinical practice.
Improved detection and early recognition of possible work-related asthma through use of a validated screening questionnaire in primary care is expected to prompt appropriate investigation and management to confirm or rule out workplace causes or aggravation of asthma.
Dr. Roma Sehmi, McMaster University
Role of Group 2 Innate Lymphoid Cells in Eosinophilic Inflammatory Responses in Atopic Asthma
A recent study reported that one in every three individuals in Ontario would receive a physician diagnosis of asthma during their lifetime. Despite the development of anti-asthma drugs, many asthmatics continue to have worsening breathlessness as they age. Investigating biological processes that cause the symptoms of asthma may reveal new drug targets to treat the continued breathlessness that worsens over time in asthmatics.
After asthmatics inhale particles to which they are allergic, their lungs become inflamed and their asthma worsens. During this process, recruitment to the lung of mature cells such as eosinophils and basophils and their precursor cells occurs. These cells, when activated release cell-derived products which damage the lung tissue and symptoms of asthma develop such as airway narrowing and mucus over production. Identifying factors/cells that promote and expand eosinophil numbers in the airways may provide a valuable target for treatment of asthma.
Using an allergen exposure model that is well established in our laboratory, we will study subjects who are induced to have an asthmatic response as a result of a controlled inhalation of an allergic compound. Understanding the role of ILC2 in the development of human eosinophilic asthma is a new and important field. By comparing activation of ILC2s and T cells, and investigating the effect of known drugs on modulating this activation, this study will provide unique drug targets that may be beneficial in asthmatics who continue to have uncontrolled symptoms despite being treated with high doses of corticosteroids.
Dr. Azadeh Yadhollahi, University Health Network
Investigating the impact of inspiratory loading on postural induced lower airway narrowing in asthma
In patients with asthma, resistance to airflow and other asthma symptoms such as coughing and wheezing are more severe during sleep. Up to 15 per cent of asthma patients have overnight symptoms at least once a week.
Recently, we showed that when supine, fluid movement out of the legs and its accumulation in the thorax has the potential to increase airway wall edema and narrow lower airways (intrathoracic), as assessed by increases in respiratory system resistance. The magnitude of airway narrowing attributable to fluid shift in the asthmatics was clinically significant. We expect the adverse effects of fluid accumulation in the thorax will be more pronounced during sleep, because decreases in pharyngeal muscle tone with sleep onset will narrow the upper (pharyngeal) airway, result in more negative intrathoracic pressure during each inspiration to overcome the increased upper airway resistance, increase intrathoracic blood volume in the heart and lungs, which can further narrow the lower airways and worsen asthma.
Our objective is to investigate whether increased upper airway resistance during inspiration with the application of inspiratory threshold loading (ITL) would affect fluid accumulation in the thorax and lower airway narrowing in awake patients with asthma.
We expect that compared to the control supine, during ITL intervention, there will be more increase in thoracic fluid volume and lower airway narrowing. We also expect that the magnitude of effects with ITL will be bigger during supine compared to the sitting posture.
If our hypothesis is confirmed, this study can lead to new understanding of why asthma symptoms worsen during night, and why nocturnal asthma is more common in patients with sleep apnea who experience cyclic collapses of upper airway during sleep. A deeper understanding of the intricate interplay between respirology and sleep is necessary to reveal new therapeutic strategies that improve the quality of life for people with these life-long disorders.
Chronic Obstructive Pulmonary Disease (COPD)
Dr. Denis O’Donnell, Queen’s University
Differential Mechanisms of Dyspnea Relief in Advanced COPD: Opiates vs. Bronchodilators
In patients with advanced COPD, breathlessness (breathing difficulty or discomfort) is the most troublesome symptom and leads to restricted activity, progressive social isolation, anxiety, depression and poor quality of life. More than 50 per cent of COPD sufferers report persistent breathlessness despite the best available medical therapy. To help these unfortunate individuals, we need to have a much better understanding of the underlying pathways within the brain and lungs that are the source of this symptom.
The objective of this project is to determine the underlying mechanisms of the activity-related breathlessness in patients with advanced COPD. We will measure:
- The drive to breathe from the brain
- The activity of the muscles of breathing during a cycle exercise test in volunteers with COPD
We will then study how these three factors are related to each other. To study the different pathways involved in causing breathlessness, we will compare the effects of two treatments which relieve breathlessness in different ways: 1) opiate medications which depress the drive to breathe, and 2) inhaled bronchodilators (puffers) which mainly improve lung function. By learning how exactly these different medications relieve breathlessness, we can discover what caused this symptom in the first place. This will be the first study to use novel advanced evaluative methods developed in Kingston to explore the underlying cause of activity-related breathlessness in COPD. The study will hopefully lead to new treatment approaches.
Dr. Warren Lee, St. Michael’s Hospital
Discovery of novel anti‐influenza drugs – a high‐throughput approach using zebrafish and mice
Influenza is one of the commonest infectious causes of death in Ontario and the threat of a novel pandemic strain of the virus persists. While antiviral drugs exist, the virus mutates rapidly and cases of resistance to these drugs have already occurred. Thus, new drugs to treat both seasonal and pandemic influenza are needed.
We propose to screen a chemical library for new compounds that will prevent death from the influenza virus. We will take advantage of the low cost and small size of zebrafish to conduct the screen of a large chemical library of compounds. We have already established that the influenza virus can infect and kill zebrafish, and we are looking for new drugs that will rescue the infected zebrafish. Once we find some drugs that appear promising, we will see whether they also rescue mice infected with influenza. Drugs that protect both zebrafish and mice will then be studied in detail to determine how they work.
We are the first to use zebrafish to screen for drugs against influenza. We also are unique in that we have a lot experience studying mouse models of influenza, allowing us to “double-check” what we find in the zebrafish. Most approaches for screening for new drugs use cells in dishes, which is not ideal because cells by themselves are not a good mimic for the whole animal.
There is only one class of drugs available for influenza and resistance has already been reported. Because the virus mutates constantly, vaccination is not always effective or rapidly available. The proposed research will identify new drugs that can prevent death from influenza in two different animal models. This will set us on the fast track to identifying new drugs that might protect human patients from the influenza virus.
Dr. Roger Goldstein, West Park Healthcare Centre
The effect of music during pulmonary rehabilitation in people with chronic obstructive pulmonary disease (COPD)
People with a longstanding lung disease are encouraged to undertake exercise training as part of their treatment. Such training will increase their quality of life. However, they often find themselves limited by breathlessness and tiredness in their legs. These barriers limit how much a person may benefit from an exercise program and how well they may keep up with a recommended schedule of exercise at home. One way of reducing feelings of breathlessness and leg tiredness is by listening to music during exercise. However, the impact of adding music to exercise versus exercise alone has not been explored in the setting of pulmonary rehabilitation.
The aim of this study is to determine the effect of listening to music during exercise sessions that are specifically designed for people with chronic lung disease on exercise capacity, symptoms, quality of life and motivation to exercise.
Music is widely used during exercise by healthy people. Music is enjoyable to many people with chronic lung disease and this study will determine whether listening during training will improve their ability to exercise, their motivation and their enjoyment of exercise. It is exploring the use of a simple, inexpensive addition to exercise training. Supervised exercise is the standard of care for those with chronic respiratory conditions. If music increases the effects of an exercise program, then an inexpensive add-on can be used to deliver an exercise program.
Dr. Sherri Katz, Children’s Hospital of Eastern Ontario
Pulmonary Disease Magnetic Resonance Imaging of Ex-preterm Children to Understand Risk of Emphysematous Changes (The PICTURE study)
Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common complication of being born too early (premature). Damage to the still developing lung stops the normal formation of the alveoli (the air sacs in the lung that allow the uptake of oxygen and release of waste carbon dioxide). Young adults with a history of BPD have lower lung function, early heart disease and increased risk of death, compared to those without BPD.
Recently, it has been reported that they may also develop a type of lung disease typically seen in older adults with a longstanding history of smoking. The severity of lung disease is usually measured using pulmonary function tests, but these tests may be normal, even in the presence of important changes in the fine structure of the lung. Such structural changes may be early markers of future lung disease and can be detected using lung magnetic resonance imaging (MRI). Unlike other ways of imaging (taking pictures of) the lungs, MRI does not expose people to harmful X-rays.
To date, no studies have been done to examine the fine structure of the lung of school-aged children who had a history of BPD, to determine whether there are signs of lung disease that might not otherwise be obvious. This is important because once armed with this information, preventive measures can be taken to avoid worsening of lung disease.
This will be the first study using MRI as an innovative way to visualize and measure fine structure of the lung in children born prematurely with and without BPD. These findings may be early markers of lung disease, which would identify children who have, or are at risk of developing lung disease later in life, and this may not be detected using lung function tests or based on symptoms. For these participants, we may be able to offer treatments now and/or prevent worsening of lung disease.
Dr. Vito Mennella, The Hospital for Sick Children
Primary Ciliary Dyskinesia Diagnosis by Super Resolution Microscopy
The cells lining the lung of the human body have tiny hair-like structures named cilia whose function is to move bacteria and foreign particles out of the nose by their coordinated wavelike movement. Appropriate cilia structure is essential for healthy human development and physiology. In fact, devastating inherited conditions happen when genes involved in cilia structure are changed.
In this proposal, we will study patients affected by Primary Ciliary Dyskinesia (PCD)—a disease also named Kartagener syndrome—a genetic recessive disease characterized by impaired motility of cilia. Babies affected by PCD present with recurrent breathing and hearing problems due to frequent infections and poor lung function, that can ultimately lead to lung failure. It is important to diagnose kids with PCD early, because it reduces their chances to progress to irreversible lung impairment. This in turn reduces the need for lung transplant, which can have devastating implications for patients, families and the health care system.
Currently, the diagnosis of PCD can be very long and inefficient, it is not well standardized and can be also inconclusive due to the inherent limitations of the technologies used for diagnosis. The objective of our research is to develop an efficient, fast and reliable method to diagnose PCD patients. By using a new imaging technique, we are creating a molecular fingerprint of cilia in normal persons, which will be compared to the one from children affected by PCD. This will allow us to identify what is missing or disorganized in the structure of cilia in sick children.
Our ultimate goal is to build a complete map of cilia and identify the structural feature(s) that underlie inherited diseases such as PCD and other genetic disease. Overall, our results will help to develop the rational for new diagnostic tools that is broadly applicable to other cilia related diseases of the lung and other genetic diseases.
Dr. Mark Ormiston, Queen’s University
Examining the impact of endothelial BMPR2 loss on immune dysfunction in the pathogenesis of pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a fatal disease affecting the blood vessels of the lung. This disease, which preferentially targets young women in their 30s and 40s, involves a loss of lung blood vessels, leading to increased stress on the right side of the heart and eventual death due to heart failure.
PAH is linked to mutations in a gene called BMPR2 and is known to be associated with the reduced function of a number of cell types, including the endothelial cells that line the blood vessels of the lung, as well as circulating cells of the immune system. Despite this knowledge, there is relatively little understanding of how interactions between endothelial cells and the immune system can impact on lung vascular structure, or the importance of BMPR2 in these interactions.
Our previous research has shown that particular immune cells, known as Natural Killer (NK) cells are impaired in PAH. The current project will test if this reduced NK cell function is due to interactions with the diseased endothelial cells from PAH patients.
This work is among the first to examine the possible contribution of NK cells to the development of PAH. It holds the potential to identify a completely original way by which diseased endothelial cells can influence the immune system and contribute to disease. Despite the approval of several new treatments for PAH, the the annual mortality rate remains high (~15%), in-line with that of stage III breast cancer. This poor survival is linked to the fact that available therapies primarily treat the symptoms of PAH and do not address the underlying factors driving disease progression.
This project holds the potential to identify previously unknown factors that drive NK cell impairment in PAH. This knowledge can then be used in the development of a new generation of therapies that target immune dysfunction in disease.
Dr. Dawn Bowdish, McMaster University
The aging microbiome as a risk factor for developing pneumococcal pneumonia in mid- to late-life
Older adults (50+yrs) are at high risk of developing pneumonia and having pneumonia in mid to late-life can accelerate or worsen the progression of other diseases such as cardiovascular disease, dementia and type 2 diabetes. Therefore preventing pneumonia will provided older adults with more years of healthy independent living.
The bacteria that is the most frequent cause of pneumonia is Streptococcus pneumoniae. Before infection this bacteria must colonize the nasopharynx, which means it binds to the cells that line the sinuses. This is generally asymptomatic but is a pre-requisite to spread to the lung, bloodstream or meninges.
Our study will investigate whether modifications in the upper respiratory tract microbiome can be altered to protect against colonization and spread of S. pneumoniae. Although studies of the microbiome are in their infancy, because the microbiome is modifiable, it is a novel therapeutic target. Currently, we do not have probiotics that are specific for the upper respiratory tract and in order to develop them we need to understand what the “good” bacteria are that are protective against infection. Once we establish this we can determine whether these good bacteria can be harnessed and developed commercially to provide a novel preventative strategy for older adults.
Because vaccination requires an intact immune system, it is not very effective in older adults. The only preventative strategy we have is to vaccinate children, in which it is highly effective to protect older adults by herd immunity. Since pneumonia remains the sixth largest cause of death in Canada, the vast majority in older adults, this is clearly not sufficient. Modifying the microbiome may be a cheap and acceptable adjunct therapy to stop S. pneumoniae colonization and thus infection.
Dr. Jeremy Simpson, University of Guelph
Unexpected progressive non-persistent lung inflammation and diaphragm atrophy following myocardial infraction
Exercise capacity and breathlessness is the chief complaint for patients with cardiac problems which significantly reduce quality of life. Respiratory muscle and lung dysfunction both contribute to reduced exercise capacity and breathlessness. Any improvements in function will be of benefit to patients with heart failure.
These experiments are aimed at identifying the exact cause for the changes we observed in the respiratory system of patients following myocardial infarction. If the current proposal is correct, we will demonstrate lung inflammation and diaphragm dysfunction following myocardial infarction. We will also identify the mechanism, which is important for developing future therapeutics to prevent or treat this disease.
Our aim is to understand the mechanism that causes the changes in the respiratory system that lead to lung inflammation and respiratory muscle dysfunction. We will also test clinically available drugs to prevent the development of lung inflammation and respiratory muscle dysfunction. Our ultimate goal is to understand how these diseases develop following a heart attack so we can find drugs or therapies to stop this progress.
Virtually nothing is known about development of lung inflammation and respiratory muscle dysfunction in the weeks following a heart attack. This work represents the first comprehensive, integrative and multidisciplinary study of the fundamental mechanisms in the development of a heart attack-induced respiratory muscle and lung dysfunction. Additionally, if the current proposal is correct, we will have evidence to support clinically available drugs to use in patients following a heart attack. If we can prevent respiratory muscle and lung dysfunction in patients following heart attack, they will be able to begin rehabilitation earlier and with better gains in recovery.
Dr. Stephen Juvet, University of Toronto/UHN
Targeting pulmonary CD103+ dendritic cells to prevent chronic lung allograft dysfunction
Lung transplantation can save the lives of people suffering from severe lung disease, and improves the quality of life. Unfortunately, most transplanted lungs are ultimately severely damaged by the patient’s immune system, even though powerful anti-rejection drugs are given. As a result, patients end up needing oxygen and puffers, and often die or need another lung transplant. Our ability to prevent this problem, which is called “chronic lung allograft dysfunction” (CLAD), is very limited with our current treatments. We need to identify new targets that will allow us to prevent CLAD from developing in the first place.
This project uses a state-of-the-art mouse lung transplant model, which is not available elsewhere in Canada. It also uses advanced immunology techniques to address the role of lung dendritic cells, which have not been studied as potential treatment targets in lung transplantation. If we are able to find an important role for these dendritic cells in the development of CLAD, it could lead to new treatments to prevent CLAD and improve the outcome of lung transplantation.
Lung transplantation is the only viable treatment option for the thousands of Canadians suffering from end-stage lung disease. Yet, its long-term success is limited by the development of CLAD, a severely debilitating and life-threatening illness, in half of patients within five years. This project will reveal how lung dendritic cells contribute to the development of CLAD, thus opening new avenues for CLAD prevention.
Dr. Niall Ferguson, University Health Network
Diaphragm Activity and Function During Mechanical Ventilation: the MYOTRAUMA Study
Mechanical ventilation is a life-saving intervention for people whose lungs are failing. Most patients recover and are able to breathe on their own after a short time on the ventilator. However, some patients require support from the mechanical ventilator for many days or weeks. One important reason for this delayed recovery is weakness of the muscles used for breathing, especially the diaphragm. Because a strong diaphragm is necessary for breathing without ventilator support, diaphragm muscle weakness keeps patients dependent on the ventilator. During this prolonged weaning from the ventilator in the ICU, patients may experience complications including delirium, infections, and death that might not occur if they could breathe on their own sooner.
Just as any muscle that is rested for too long will get weak, previous research in animals and in ventilated patients suggests that mechanical ventilation may rest the diaphragm too much and make it weak. Some studies also suggest that providing ventilator breaths that are out-of-sync with the diaphragm contractions will also weaken this important breathing muscle. We want to confirm whether these findings are true in patients. If true, then while mechanical ventilation is life-saving in the short term, it may actually prevent patients from recovering from respiratory failure.
This study will be the first to directly examine whether too much diaphragm rest and out-of-sync breathing can cause diaphragm weakness in patients on ventilators in the intensive care unit. The results of our study will be used to design a new ventilation strategy to prevent diaphragm weakness and reduce prolonged dependence on ventilators with its known complications helping patients to recover from lung failure more quickly and improve their long-term recovery.
Other areas of lung research
Dr. Arun Ramchandran, University of Toronto
Embolus on a chip: A new experimental model to study the lysis of occlusive thrombi
Pulmonary Embolism (PE) occurs when an embolus, which is a fragment of a blood clot, is carried by blood into the vessels of the lung, and lodges there. It becomes life threatening when the blood supply to the lungs is cut off. In acute cases of PE with low blood pressure, the established therapy is to introduce a clot-dissolving (thrombolytic) drug in the blood. This decreases the size of the embolus by breaking it down, thus facilitating blood flow and improving heart function rapidly. For acute PE without low blood pressure, which constitutes about 30 per cent of PE cases, there is vigorous debate and uncertainty in the literature over the use of thrombolytic drugs. This is in spite of demonstrated potential advantages of quick restoration of blood flow, reduced post-traumatic syndrome, low recurrence rates, and reduced mortality rates for patients with adverse prognosis. The root cause underlying this reservation is the poor molecular and physical understanding of the mechanisms of embolus dissolution by drugs, which we plan to investigate.
The overall objective of this project is to develop fundamental understanding and provide new insights on the effect of biophysical properties and structure of embolic clots on their dissolution with clot‐digesting drugs. Preliminary data suggest that the extent of deformation, the stiffness, and the change in structure of embolic clots strongly influence the flow of fluids through them, which results in the change of the rate of clot dissolution. The purpose of this project is to apply a new in-vitro model called ‘Embolus-on-a-chip’ to explore these effects.
This project will provide fundamental understanding of how emboli, which are compressed clots (different from normal clots), dissolve when subjected to a thrombolytic drug. This knowledge will allow the design of drugs and regimen that will digest emboli quickly with lower risk of bleeding, thus allowing more effective treatment of PE for affected Canadians.
Dr. Bernard Thébaud, Ottawa Hospital Research Institute
Patient-derived induced pluripotent stem cells for the correction of surfactant protein B deficiency
The lung is made of pipes (conducting airways) that deliver oxygen to millions of air sacs (alveoli) where oxygen is taken up by the blood and distributed to the rest of the body. These air sacs are coated with surfactant produced by lung cells. Surfactant keeps the air sacs wide open to ensure exchange of oxygen. Surfactant is made out of a mixture of proteins and lipids. Amongst these surfactant proteins (SP), SP-B and SP-C decrease lung surface tension to keep the alveoli wide open. Unfortunately, there are rare but lethal genetic diseases in which SP-B is abnormal. Babies born with SP-B deficiency have trouble breathing at birth because the alveoli are crumpled and cannot open. These babies usually die. Currently, there is no therapy except lung transplantation, which is not always possible.
Our body contains stem cells, a pool of cells that have the ability to become any type of cell (i.e. bone, muscle, brain or lung cell). The “best” stem cells we know about so far are embryonic stem cells because they can become any type of cell in the body, but there are ethical, social and technical issues with these types of stem cells. A major discovery was achieved in 2006 (and rewarded with the Nobel Prize in 2012) when researchers showed that one could turn a skin cell into an embryonic-like stem cell. These cells are called “induced pluripotent stem cells” or iPSCs. It is now possible to make stem cells from any patient with a genetic disease. The objective of our project is to test if iPSCs that have been transformed into lung cells can correct the surfactant deficiency.
In this project, we will take healthy human iPSCs, instruct them to become lung cells that produce surfactant and deliver these cells into SP-B deficient mice. Then we will verify if these cells restore normal breathing and produce surfactant in these mice. iPSCs represent a promising, unique and innovative way to replace the deficient lung cells and discover a new treatment for devastating genetic disorders such as surfactant protein deficiencies. If the herein proposed research works, we will test if we can fix the mutation in iPSCs from patients with SP-B deficiency, then give this now corrected cell back to the patient in the hope that these cells will stay in the lung and function normally.
Our study will provide proof-of-concept for the feasibility, safety and efficacy of such an approach. Our study has the potential to save the lives of babies worldwide. Importantly, the results of our study will be relevant to other life-threatening genetic lung diseases that currently lack treatment options.
Dr. Sarah Wootton, University of Guelph
Nuclease-based gene targeting for correction of alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin (AAT) deficiency is a genetic disorder commonly associated with adult onset lung diseases, including emphysema, chronic obstructive pulmonary disease (COPD) and airway inflammation. The AAT protein is normally made in the liver, and in addition to lung related disease, a subset of individuals with severe AAT deficiency are at risk to develop serious liver complications.
Treatment options for AAT deficiency include inhaled bronchodilators and steroids, pulmonary rehabilitation and in the more severe cases, lung transplant. These treatments however, only address the symptoms of AAT deficiency, but do not address the underlying cause (i.e. defective AAT protein). Protein replacement therapy is also available to people with AAT deficiency associated lung disease and consists of weekly intravenous infusions of normal AAT protein purified from healthy blood donors. While this approach may be effective for lung-related AAT disease, protein replacement therapy does not address liver related disease. Additionally, the requirement for weekly infusions for life, along with the high cost of this therapy makes it an unsustainable option.
A promising alternative treatment for AAT deficiency is gene therapy. The idea behind gene therapy is to provide an individual who has defective copies of the AAT gene, with a functional, good copy of the gene. We plan to engineer a harmless insect virus to deliver all the “tools” required to integrate a functional copy of the AAT gene into liver cells. Our approach will not only deliver a good copy of the gene, but will also suppress the bad copies. By delivering a good copy of the gene we can cure the lung related disease, and by suppressing the bad copies, we can cure the liver related disease.
By developing novel gene therapy approaches to efficiently deliver the genome editing nuclease, CRISPR, along with its donor template, we can potentially cure a wide variety of genetic diseases such as AAT deficiency, cystic fibrosis and haemophilia. Results from these experiments will also assess whether a dual function gene therapy vector could be useful for the treatment of Z-AAT induced liver disease.