Respiratory Diseases
Two genetic diseases of the respiratory tract appear amenable for treatment by gene and cell therapy: cystic fibrosis and alpha1 anti-trypsin deficiency. Cystic fibrosis is caused by one of 1,400 mutations in a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR). Its discovery ignited high hopes for a rapid cure of cystic fibrosis by gene therapy. Various gene transfer vectors that express CFTR have been tested in one or more gene therapy clinical trials, and 20 trials have been completed to date. Although the observed efficacy was minimal, the recent trials exhibited a good safety profile and focused the scientists on challenges necessary to provide sufficient, long-term CFTR expression in the lung. The progress and status of gene and cell therapies for these respiratory diseases are summarized here.
Most patients born with respiratory diseases are not able to breathe as easily as healthy people. The most common genetic respiratory disease is cystic fibrosis. Although cystic fibrosis affects other organs (pancreas, liver, gallbladder, sweat glands, and intestines), lung disease usually causes the most discomfort and is ultimately responsible for the death of the vast majority of CF patients. Cystic fibrosis is caused by mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). Both copies of the CFTR gene inherited from the father and mother must have mutations to get the disease. Most patients (70%) harbor the same, very common, mutation in CFTR. The large CFTR protein is present in the cells that compose the lung tissues called epithelial cells, which are the cells lining the airways in the lung. The CFTR protein helps epithelial cells regulate the passage of salt and water across the epithelial layer. Therefore, patients with cystic fibrosis have altered concentrations of specific salt molecules (such as sodium and chloride) in their lungs. The observation that people with one normal CFTR gene have normal lung function indicates that expression of at least half the amount of normal CFTR in all relevant cells would reduce or eliminate the symptoms. However, gene therapy studies have suggested that this threshold for correction may be much lower—expressing CFTR in as little as 6-10% of airway epithelial cells fully correct chloride transport abnormalities. The discovery of the CFTR gene ignited high hopes for a rapid cure of cystic fibrosis by gene therapy. Various vectors that express CFTR have been tested in one or more clinical trials, and 20 trials have been completed to date. Although the recent clinical trials have demonstrated safety in the treated patients, minimal efficacy was evident. Most scientists agree that the ideal vector would efficiently target relevant epithelial cells of the lungs, express sufficient CFTR protein, hide from the immune system, remain invisible to the inflammatory cells, and be sustained in the cells or organ for years. Alternatively, a vector that maintains sufficient expression by repeated administration would be acceptable. Scientists are investigating viral and non-viral vectors to develop the ideal vector with these characteristics. The airways have evolved many ways to protect against the outside environment, and these mechanisms hinder gene transfer to lung epithelial cells. These challenges include airway mucus, specific sugar molecules that block binding of viruses or vectors, and an army of immune cells and inflammatory cells that can intercept any foreign viruses or substances. These same protective mechanisms can hinder the uptake of the gene therapy agent. Progress and challenges of treating cystic fibrosis with gene therapy were summarized in this review article (Everett & Johnson 2009).
Most cases of alpha1 anti-trypsin deficiency are associated with 1 of the 100 mutations found in the Alpha1 anti-trypsin gene. Two copies of this low producing allele (Z) results in an alpha1 anti-trypsin protein level ranging from 3.4 – 7µmol/L, which is significantly lower than the 40-53µmol/L level in normal people. This variant of the alpha1 anti-trypsin protein folds in an abnormal manner and this altered structure prevents its release from liver cells, which can cause liver cell death. The severity of alpha1 anti-trypsin deficiency is variable. For example, the null allele does not produce any alpha1 anti-trypsin protein, increases the risk for emphysema, and causes no liver disease as there is no protein to over-accumulate. The more severe cases show symptoms of emphysema, chronic obstructive pulmonary disease (COPD), and occasionally chronic liver disease. People who carry one normal allele and one null allele have no symptoms and express about one third (35%) of the normal level of alpha1 anti-trypsin. Scientists face similar challenges in designing the ideal vector for the long term expression of alpha1 anti-trypsin as cystic fibrosis. Because alpha1 anti-trypsin is a secreted protein, the site for delivery of the gene therapy vector can be an alternate site instead of the liver or lungs. A phase II trial is assessing the safety profile and efficacy of intramuscularly administering an AAV1 vector that carries the alpha1 anti-trypsin gene to patients with alpha1 anti-trypsin deficiency. The results from this and previous trials are helping to develop a gene therapy treatment for patients with severe alpha1 anti-trypsin deficiency.
A combined gene and cell therapy strategy is also being explored for treatment of cystic fibrosis and alpha1 anti-trypsin deficiency in animal models. The concept of such a therapy is as follows. Basically, the stem cells from the patient would be treated with a gene therapy agent that will allow the expression of a normal copy of the mutated gene. The cells would then be allowed to grow in number and transferred back into the patient. To meet these goals, ongoing scientific research is identifying the relevant stem cells, developing methods for their successful harvest or maturation, engineering vectors with the appropriate characteristics to maintain long term expression of this gene, and reduce detection of the corrected cells by the immune and inflammatory cells that could potentially eliminate them. After appropriate testing in tissue and animals, these studies can eventually lead to combined gene and cell therapy strategies for the treatment of cystic fibrosis and alpha1 anti-trypsin deficiency.
Everett, R.S. and Johnson, L.G. Progress Toward Gene Therapy for Cystic Fibrosis. In: Gene and Cell Therapy: Therapeutic Mechanisms and Strategies. (Third Edition, N.S. Templeton, ed.) CRC Press, 2009, pp. 813-831.
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