Pharmacogenetics, Pharmacogenomics and Gene Therapy
The completion of a draft of the human genome has led to a revolution in the use of genetic information to study the pathophysiology of airway disease. There are three major potential uses of genetic information. First, knowledge of the precise sequence o
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Division of Therapeutics, University Hospital of Nottingham, D Floor, South Block, NG7 2UR, UK e-mail: [email protected]
Introduction . . . . . . . . . . . . . . . . . .
288
2
Pharmacogenetics and Airflow Obstruction
288
3
Genetic Variability: General Considerations
290
4
Genetic Variability in Airway Targets . . .
291
5
Genetic Variability and Pharmacokinetics
292
6
PrAdrenoceptor Polymorphism.
292
7
Muscarinic M2 and M3 Receptors
294
8
5-Lipoxygenase Activity and Cys-Leukotriene 1 Receptors
294
9
Glucocorticoid Receptor Polymorphism
295
10
Phosphodiesterase Inhibitors
295
11
Pharmacogenomics .
296
12
Gene Therapy
297
13
Summary.
299
References . . .
299
Abstract The completion of a draft of the human genome has led to a revolution in the use of genetic information to study the pathophysiology of airway disease. There are three major potential uses of genetic information. First, knowledge of the precise sequence of genes can be used to develop gene therapy approaches for the management of airway disease. Second, expression profiling approaches can be used to define novel targets for therapy. Third, genetic variation in the key targets for drugs used in the management of airway disease might account for inter-individual variability in treatment response. Keywords Pharmacogenetics· .Bz-Adrenoceptors . Expression profiling . Cystic fibrosis . a 1- Antitrypsin deficiency
C. P. Page et al. (eds.), Pharmacology and Therapeutics of Asthma and COPD © Springer-Verlag Berlin Heidelberg 2004
288
1. P. Hali
1
Introduction
Whilst most patients with asthma and/or COPD will exhibit good disease control with conventional medication, there is considerable interindividual variability in response to specific treatment. In addition, a small minority of patients will have disease which responds poorly to medication. With the near completion of the working draft of the human genome, a wealth of genetic information has become available which will enable novel approaches to patient management to be considered. In this chapter, three different approaches involving the use of genetic information will be reviewed. First, the potential contribution of genetic factors to variability in treatment response in asthma and COPD will be considered. Second, the use of genetic approaches for novel target identification (pharmacogenomics) will be reviewed. Finally, an outline will be provided of the potential value of gene therapy approaches to the management of asthma and/or COPD. 2
Pharmacogenetics and Airflow Obstrudion
Many factors will influence whether or not a given individual responds to a specific treatment. Whilst issues such as compliance and environmental exposure are obviously important, a major component contributing to interindividual variability in treatment response is likely to be genetic factors. In broad terms, these can be separated into factors which affect the pharmacokinetic profile of a drug (e.g. genetic variability in drug metabolising enzymes) and factors which affec
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