Format:
1 Online-Ressource (26 Seiten)
ISBN:
3527620982
Content:
The human reference genome has been sequenced, and progressing research in the post-genome era is revealing the impact of genetic variation on fitness. Human genomes are more than 99% identical, but less than 1% variation determines genetic differences between individuals. Over 80% of this variation is due to single nucleotide polymorphisms (SNPs). These alter the sequence in the genetic code by changing single bases. Two out of three SNPs are cytosine to thymine (C→T) transitions. More than 11 million SNP positions are believed to be present in the entire human population. Of these, about 3 million differ between any two given individuals. A portion of these SNPs is located in exons and/or regulatory elements, which can lead to changes in the amino acid sequence of resulting proteins, or affect gene activity. This is a major cause for different individual responses to drugs and environmental substances. Furthermore,SNPs can determine the presence of susceptibility alleles and, therefore, genetic predisposition for hereditary diseases. Most SNPs do not influence cell function, but those that do are of high value for biomedical research. Currently, the focus of academic medical research and the pharmaceutical industry is on metabolic enzymeswhich control drug activity and on structural proteins which change disease susceptibility (see also Part I, Chapter 2). To determine the large amount of base variation in the human genome reproducible, fast, and economical techniques are required. Array-On, an innovative German biotechnology enterprise, has developed an extremely precise high-throughput DNA chip-based technology for SNP typing. Two patents were granted: a novel hybrid spotting technique for microarrays and appendant areal arrays that are part of a solidphase primer extension approach for automated SNP detection. The main advantage of the new technology is that numerous individuals can be screened for various SNPs on a single DNA chip without crosstalk between individual probes and samples. The ability to examine the same genes in a large number of individuals in one miniaturized reaction chamber leads to great savings in materials and time. The number of individuals and SNPs analyzed on a single chip can be combined in a most flexible manner, and up to 50 000 simultaneous allele calls are possible. Even orthologous genes of different species may be analyzed and compared on the same microarray. The so-called polydimensional SNP chip will, among other techniques, contribute to the develop-ment of safer and more effective medicines which will address unmet medical needs and be available faster with enormous savings. The creation of medicines with approved risk-benefit ratios, in particular with reduced unwanted side effects or adverse drug reactions (ADRs) and higher personalized efficacy, seem to be reachable with pharmacogenetic approaches. Major research efforts are still necessary to fulfill the promises of pharmacogenetic testing in the future. It is already expected that regulatory authorities will ask for SNP genotyping not only to reduce clinical trials in size and time but also to reduce the risks for participants. The goal is to generate genetically associated drug targets with a break-through for the development of first personalized medicines, and the better control of generalized drugs bearing high risks for patients with certain genetic backgrounds. This article provides an overview: 1) of the latest pharmacogenetic findings; 2) of validated SNPs ready for the implementation in pharmacogenetic programs; 3) of state-of-the-art SNP technologies and detail about the Array-On technology; and 4) the future potential of pharmacogenetics in the drug developmental process.
In:
Modern biopharmaceuticals, Weinheim : Wiley-VCH, 2005, 1(2005), Seite 71-98, 3527620982
In:
9783527620982
In:
volume:1
In:
year:2005
In:
pages:71-98
Language:
English
DOI:
10.1002/9783527620982.ch3
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