Chemnomics

Systems Biology in Action

September 14, 2008

Bruce Tomczuk, PhD

In the past entries, I have described my analysis of the woes of the pharmaceutical industry and I have detailed solutions, stressing the necessity to switch to a systems biology approach toward disease treatment.  In this entry, I ] extract examples from an article written by Lisa M. Jarvis in the September 1, 2008 issue of Chemical & Engineering News, on systems biology in action.

In this article, Jarvis delineates systems biology approaches to a treatment of Cystic Fibrosis.  The first example describes the early work of Aurora Biosciences which was later acquired by Vertex, who continued the project.  The project was based on the discovery that CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.  This mutation causes an excess absorption and a decreased secretion of chloride ion which prevents the formation of a critical thin film of hydration.  Consequently, the lungs suffer a defect whereby dry pockets develop that get clogged with thick mucus and provide a breeding ground for bacterial infections.

The Aurora project

Thus, the original Aurora project set out to discover “correctors”, that is, compounds that could increase the number of chloride ion channels as well as “potentiators”, compounds that could increase the flow of chloride ions through existing chloride ion channels.  Note, the phenotype descriptions in quotations!  The research strategy didn’t rely on the molecular mode of action of the compounds, just the resultant phenotypic action.

Cut to the chase, after several years of research, Vertex is currently conducting clinical trial with VX-809, a “corrector” in Phase I and VX-770, a “potentiator” in Phase II.  These compounds have the potential to not only provide symptomatic relief but also modify the disease.  The project had taken on a life of its own as Joshua Borger, CEO of Vertex, has stated that “[he] couldn’t stop this project if [he] tried”.  Preliminary clinical results of VX-770 have shown that after just two weeks of treatment, not only was lung function improved, but the amount of salt in their sweat was also lowered which demonstrates the systemic disease modifying effects of the drug.  Again, the exact molecular mechanism of action of VX-770 is not completely understood, but the importance is that the biological activity of the drug corrects the defect underpinning the disease.

It is interesting to note that on a parallel track, the Vertex compounds have provided the tools to further dissect the nature of the disease: how the CF protein folds, which partners it folds with, and where it self-interacts. 

The PTC Therapeutics project

A second project that highlights the wonders of systems biology is PTC Therapeutics.  Scientists with this project uncovered that in a smaller subset of CF patients, there is a “nonsense” mutation, a premature stop signal on the mRNA that causes the ribosome to fall off before the full CTFR protein is produced.  PTC Therapeutics used a systems biology approach to look for compounds that would allow the normal CFTR protein to be produced.  This approach was based on the fact that gentamicin and other aminoglycosides could already elicit such an effect, albeit weakly.  PTC utilized a HTS screen based on a cellular assay producing firefly luciferase from LUC nonsense-containing mRNAs expressed in HEK293 cells.  The screening hits were optimized to yield PTC124 via traditional medicinal chemistry techniques except that the SAR followed “nonsense suppression activity”.  Again, although the exact molecular mechanism of action of PTC124 is unclear, the compound appears to bind to the 28S ribosomal submit to induce a conformational change that enables the full translation of the CFTR protein.

Encore

These are just two examples that utilize a systems biology approach to successfully discover new drugs.  Some of these drug candidates have progressed to proof-of-concept in patients with potential for disease modifying treatments.  Similar approaches could be used for any disease, and I have expanded on some approaches in previous entries.  In my opinion, this is the strategy for successful drug discovery and one which must be implemented ASAP.

Note: The author (BT) declares no financial ties to PCT Therapeutics or Vertex Pharmaceuticals, Inc.