Ushering in the era of personalized healthcare

Next-generation sequencing and genomic enrichment arrays facilitate new research approaches for drug discovery and disease management.

The rising costs of bringing a drug to market and the cost pressure under which healthcare systems operate has created an environment in which the development of successful drugs has become increasingly challenging. In order to grow profitability, pharma must focus on both reducing the costs of drug development and on increasing the medical value for segmented patient populations. Flexible solutions are required to address the needs of the drug discovery process and support downstream clinical trials. Next-generation sequencing coupled with genomic enrichment technologies offer new research solutions for more efficient pharmaceutical and diagnostic development.

The genomics revolution
Genetics play a large role in human health and DNA sequencing has proven to be an important tool in understanding the genetic basis of disease. However, the cost and resources needed for capillary (Sanger) sequencing has limited the scope of genomic analysis of disease. The next-generation sequencing era, marked by the commercialization of the Genome Sequencer System from 454 Life Sciences in 2005, triggered a fundamental change in the way researchers approach personal genetic variation. Rather than analyzing a single sample at a coarse level, the speed and throughput of next-generation sequencing systems enables scientists to study hundreds of samples at significant depth and quality. With the introduction of genomic enrichment technologies, such as Roche NimbleGen’s Sequence Capture Array products, the time and cost of sequencing has decreased further as it is now possible to capture and sequence only the human genomic regions of interest. These arrays target specific candidate gene or exon sets, the whole human exome, and contiguous disease-associated regions. The combination of the 454 Sequencing System and NimbleGen Sequence Capture arrays has created a paradigm shift for the analysis of variants within genomic loci and megabase sized disease regions that play critical roles in human health. The challenge is now to rapidly and accurately apply these technologies to understand how disease-associated genetic variation can ultimately lead to powerful discoveries of new drug targets.

Accelerating Discoveries
These technologies enable innovative approaches to develop novel therapies and diagnostics and are considered one tangible pathway towards personalized healthcare in the future. Recent studies have used the 454 Sequencing System alone or in combination with NimbleGen Sequence Capture Arrays to uncover new insights into the genetic basis of a wide range of diseases, including:

• Oncology – In a pivotal paper published in Nature Methods in 2006, Thomas et al. demonstrated that the 454 Sequencing System could be used to elucidate cancer tumor microheterogeneity. The study identified two minority EGFR populations at a frequency of 2% and 3% of the total EGFR, both of which were associated with clinical resistance to EGFR inhibitor drugs. In another study, the combination of the 454 Sequencing System and NimbleGen Sequence Capture Arrays was used to analyze specific exons in a lymphoma cancer cell line (Albert et al. Nature Methods, 2007). The study demonstrated the effective capture of exons with high coverage of the targets.
• Viruses & Infectious Diseases – The throughput of the 454 Sequencing System has allowed researchers to deeply analyze viral populations and identify viral subtypes. Recently Simen et al. (Journal of Infectious Disease, 2009) used ultra-deep sequencing to identify low-frequency drug-resistant HIV variants in patient samples. The study found that mutations present at the 1% level likely lead to premature failure of treatment. Identifying these rare viral mutations may ultimately enable prescription of a more effective drug regimen and sophisticated surveillance based on an infectious agents’s genetic characteristics.
• Autoimmune Diseases – In another recent study, Nejentsev et al.(Science, 2009) outline a path from genetic association to the identification of protective and causative alleles for type 1 diabetes, marking a key step towards the development of clinical applications based on previously identified molecular markers.

Next Generation Sequencing in the Clinical Setting
While there is still tremendous progress to be made towards the dream of personalized healthcare, current medical research demonstrates the power of the next-generation sequencing and genomic enrichment technologies to uncover the genetic basis of human disease.

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