The Proceedings of the American Thoracic Society 1:294-295 (2004)
© 2004 The American Thoracic Society
Chairman's Summary
Colin T. Dollery
The 2004 Transatlantic Airway Conference (TAC) had an unusually wide brief in reviewing gene and drug therapy of the lung. Although this did not allow any one topic to be covered in great depth, it provided some fascinating insights into complex issues that need a matrix approach to solve them.
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GENE THERAPY
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The airways are exposed to a torrent of alien DNA in inspired air ranging from human nasal and bronchial secretions to pollens, house dust mite feces, animal danders, and flying insects. It is no surprise that the airways are well defended against the risk that alien DNA may reach the nuclei of airway cells and induce them to express the proteins that it encodes. These defense mechanisms are obstacles that must be overcome in inhalational gene therapy for lung disease. The barriers are many and include: (1) delivery to a distal lung site in a congested and obstructed airway—a topic covered in more depth under particulates; (2) access to the target cells, some of which lie in mucosal glands, not on the surface; (3) entry into the cytoplasm of a large and insoluble piece of DNA; (4) passage from the cytoplasm into the nucleus; and (5) stable, and ideally controllable, expression of the encoded protein.
At a symposium I attended 10 years ago a leading molecular biologist declared, roundly, that we were "nowhere" in achieving any of these objectives. It is in some ways disappointing how little progress has been made in the interval—but there has been some. It has proved possible to transfect the nasal mucosa of mice with cystic fibrosis DNA using liposomes as a delivery vehicle, but the efficiency is so low that most discussants at the TAC doubted that this was a viable approach. Mechanical, electrical, or chemical techniques that cause a transitory increase in permeability can increase efficiency, but their practicality for use deep in the human lung is doubtful. Viral vectors including adenoviruses, adeno-associated viruses, and paramyxoviruses can achieve higher efficiency because they carry the biochemical machinery to deliver a relatively large payload across both the cell membrane and the nuclear membrane. But viruses have serious problems. The human immune response makes repeated administration problematic—although the extent of this problem varies with the virus. Virus-transfected cells may have reduced viability or become the target of killer T cells.
Barring a tangential discovery—never to be discounted in science—a step-by-step approach will be necessary, probably using viral mechanisms for crossing the cell and nuclear membranes, but not a complete viable virus. Another suggestion was that ligands to internalized G protein–coupled receptors could be used, although there was doubt about the size of the possible payload. One discussant suggested moving the gene through the membrane in pieces and reassembling it in the nucleus—akin to the building of the space station in orbit and probably fraught with comparable levels of difficulty. Another discussant commented that we need something like a hundredfold improvement in transfection efficiency before we shall have an effective therapy.
But the need is very great and the efforts will continue. In a deadly disease such as cystic fibrosis and in other chronic airway diseases, even a small therapeutic benefit would be adopted speedily, but it would be a bold scientist who would predict if and when that will happen.
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DRUG THERAPY
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In the late 1960s the British Medical Research Council set up a committee to investigate the increase in deaths from asthma that took place in the United Kingdom at the time. Its work focused on the favorable and, potentially, adverse effects of ß-adrenergic agonists, glucocorticoids, and with the underlying pathology in the airways. Much the same issues were covered in the 2004 TAC. There has been a great deal of incremental progress—the drugs are better; the delivery systems are better; our understanding of the disease pathology is better; and the way we treat it, earlier and with drug combinations, is better—but our fundamental understanding still has important gaps.
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IMAGING
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Knowledge of the penetration of inhaled particles into the normal lung and their deposition by impaction and sedimentation has improved considerably, driven as much by environmental pollution concerns (e.g., particulates in diesel exhaust) as by therapeutic considerations. Imaging methods have greatly improved, although functional imaging has lagged. One of the things we would most like to know in asthma and chronic obstructive pulmonary disease is whether treatment is reducing inflammation in the smaller airways beyond the reach of biopsy. The problem is that the metabolically active zone of cells in the airway walls is thin and surrounded by the massive blood pool in the lung parenchyma, and this makes positron emission tomography difficult to deploy successfully. Several discussants noted that cardiologists have achieved reasonable definition of the main branches of the coronary circulation with gated magnetic resonance imaging and were taking pictures from inside the main divisions of the coronary circulation. They asked why comparable progress in the smaller airways of the lung was so slow?
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MACRO PROBLEMS IN THE OBSTRUCTED LUNG
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Studies with radioactive gases as well as conventional physiology have shown that ventilation is often very unevenly distributed on a macro scale in asthma and chronic obstructive pulmonary disease. If a segment of lung is poorly ventilated, entry of an inhaled therapeutic agent will be restricted or virtually nonexistent. But such areas are those that are most in need of therapy. Several suggestions were made about how drugs might reach them.
One possibility is that glucocorticoids that are absorbed systemically reach obstructed areas in sufficient concentrations to exert an antiinflammatory effect. It was noted that some individuals with severe asthma who are refractory to quite high doses of inhaled glucocorticoids may respond to low doses of oral prednisone, so the systemic plasma concentrations required for therapeutic activity may not be very high. The present generation of inhaled glucocorticoids is systemically bioavailable from the lung, and these glucocorticoids clearly exert a modest systemic effect as they cause some suppression of endogenous cortisol production. Efforts are being made to produce glucocorticoids that are rapidly inactivated in the blood stream, but there is the possibility that these may be less effective in areas where their activity is most needed.
Another possibility is that there is local diffusion of drugs deposited in large airways into smaller ones. The main difficulty with this hypothesis is that the flow of blood and lymph in the bronchi is away from the periphery and toward the hylum—the opposite direction to that required. A possibility, just worth considering, is that the fluid layer above the cilia in the bronchial epithelium is so vigorously stirred by the ciliary action, or massaged by the inflation and deflation of the lung, that drugs dissolved in it can progress toward the periphery much faster than by diffusion. The fact that particulates and mucus on the surface flow along the surface in streams and rivers propelled by cilia does not necessarily require that the thin fluid layer behaves exactly the same.
Mechanisms whereby poorly ventilated areas can be treated deserve detailed study, although inhaled combinations of bronchodilators (to open the blocked airways) and steroids have helped address the problem.
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MICRO SCALE PROBLEMS IN THE LUNG
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Superficially topical treatment of the airway with inhaled particulates appears straightforward. The particles are deposited on the fluid layer and sink into it rapidly due to the low surface tension because of the presence of surfactant. Once in the fluid layer the particles dissolve (more or less rapidly depending upon their solubility), diffuse across the bronchial epithelium, and are swept away by the blood flow. For a compound that is both water-soluble and membrane-permeable, this process takes place rapidly and that is not ideal for a drug intended to have a long duration of effect in the lung. Various strategies have been used successfully to prolong the residence time, for example, making the drug relatively insoluble in water or designing it to bind to cellular components in the bronchial epithelium.
Delivering drugs by inhalation achieves a substantial degree of selectivity because the airways are exposed to a much higher concentration than other tissues. However, inhaled drugs are highly bioavailable either by absorption from the lung or after swallowing when swept out of the lung by ciliary action. Considerable progress has been made to minimize systemic effects by designing drugs to have a high metabolic clearance in the liver. This means that a high proportion of the swallowed drug is destroyed presystemically at the "first pass" and drug absorbed from the lung into the systemic plasma is relatively rapidly metabolized. It is interesting that the next logical step, designing drugs to be destroyed rapidly in the blood stream, sharply reduced their efficacy in the lung. This raises the issue that the main target of most drugs inhaled into the lung is not the surface epithelium or mucosal mast cells, but T cells and smooth muscle that lie within a vascularized milieu in the bronchial wall. Very rapid inactivation in blood may reduce the local availability of inhaled drugs to deeper structures to a substantial extent.
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SAFETY
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Delivery of drugs by inhalation exposes the bronchial epithelium to very high local concentrations. The safety of ß-adrenergic agonists and glucocorticoids by this route is attested by long experience. As interest grows in the pulmonary delivery of therapeutic agents designed for a systemic effect (e.g., insulin), their potential for local adverse effects upon the airway mucosa will become of increasing interest. What is the fate of the 50 to 60% of an inhaled drug that is deposited in the larger airways? Will peptides be broken down by exopeptidases or may they be denatured or aggregated, processes that might render them immunogenic? What may be the local effects of potent new chemical entities that may be persistent in the lung because one of the main reasons for considering an inhaled route may be their very low water solubility?
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MODELING
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The main message of the 2004 Transatlantic Airway Conference is that gene and drug delivery into the lung involves complex scientific issues worthy of detailed scientific study by both industry and academia. We know surprisingly little about the details of what happens after a patient inhales a drug into the lung. There is a need for better measurements on both the macro and the micro scale, but this could usefully be supplemented by sophisticated mathematical modeling. I always remember the advice once given to me by the distinguished American pulmonary physiologist, Herman Rahn: "If you can't measure it, calculate it." A combination of better measurements and physiologic system mathematical modeling may unlock a new era of understanding of inhaled therapeutic agents in the lung.
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FOOTNOTES
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Conflict of Interest Statement: C.T.D. retired in 1996 as Dean of the Royal Postgraduate Medical School of the University of London and since then has worked, virtually full time, as a senior scientific adviser to Research and Development in GlaxoSmithKline PLC and he is also Treasurer of the Academy of Medical Sciences in the United Kingdom and an active participant in its Forum with industry, but receives no remuneration for this activity.
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GENE THERAPY
DRUG THERAPY
