Drug Development in the Era of Genome Analysis Applied Genomics

From SNP maps to individual drug response profiling, the human genome sequence should improve diagnostic testing for disease-susceptibility genes and lead to individually tailored treatment regimens for individuals with disease. Recent analyses (from both the public and private sector) suggest that the abundance of anticipated drug targets will dramatically increase pharmaceutical R&D costs. For example, it has been suggested that a threshold investment of $70-100 million will be required if companies are to profit from recent advances in bioinformatics. However, this investment may not yield a near-term return because current validation/development methods for drug targets are insufficiently robust to add value to R&D pipelines. Competitive considerations require companies to couple considerable infrastructure investment with cost-effective validation and/or development technology that has yet to be developed.

As described above, with advances in technology, the rational design and validation of new therapeutics increasingly will rely on the systematic interrogation of databases that contain genomic and proteomic information. One can imagine three pathways from database discovery to a validated product prototype, as shown in Figure C.2.

For Pathway 1, rational small-molecule design, the methods for developing a small-molecule prototype are well established in the pharmaceutical industry, which reduces risk. However, it is not clear that small-molecule drugs can be designed, as shown above: the notion currently is without precedent (with perhaps the exception of inhibitors of HIV protease and influenza neuraminidase), and therefore is best considered as an unproven hypothesis.

A major advantage for Pathway 2, recombinant protein/peptide design, is that small-molecule prototypes need not be designed and validated at all, which may significantly accelerate product development. However, therapeutic peptides and recombinant proteins are generally ineffective when administered orally, and alternative routes of administration are generally associated with challenges in terms of formulation, compliance, efficacy, and safety.

Figure C.2. Three pathways of drug discovery and development in the bioinformatics era.

A major advantage for Pathway 3, gene therapy design, is that one may proceed directly from database query to gene-based prototype — in theory, the shortest route to product validation and development. However, gene therapy is an early-stage technology, with known challenges in erms of efficacy and safety.

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