Are stem cells ready as a next generation drug discovery tool?

Mon, December 20 2010, 12:00 AM
Posted By: Sciclips

In recent years, there is a considerable push in adopting stem cell based assays as a drug discovery tool. The major argument behind this initiative is stem cells can differentiate into specific cell types, which can be used for targeted drug screening. Major pharmaceutical companies and public funded academic institutes have been started investing significant amount of effort and money on stem cell based drug discovery with the hope that this approach will ultimately provide real breakthroughs in drug discovery research as well as significant cost savings. There is no doubt that stem cells may offer unique opportunities in drug discovery, but the scientific data to support this notion may not yet well established to the extent that is applicable to drug discovery screening. A most popular application of stem cells is the use of stem cell derived cardiomyocytes as a screening tool for testing cardiac toxicity of drugs. One can argue that there is enough scientific evidence to prove that stem cell differentiated cells are genetically similar to corresponding normal cells and can be used as a drug screening tool. This may or may not be true based on answers to following questions. a) can stem cells be a better tool in drug screening assays than currently used cell/animal based assays? b) are stem cell derived cell/tissue types are genetically and physiologically identical to the desired natural cell types, for example cardiomyocytes? c) are these proposed stem cell based assays will provide better tools to reduce or eliminate fatal side effects of drugs, e.g. cardiotoxicity? It is important to note that current use of cell based assays (non-stem cell based) failed to reduce or prevent fatal side effects of drugs. Based on this, it is hard to argue that currently proposed stem cell based assays provide any better solution to current problems. We need to understand genetic and physiological make up of stem cell derived cell types before we adopt this technology for making life saving decisions. In any means, our opinion does not imply that stem cell based products are not suitable for developing drug discovery assays. Our goal is to critically analyze the scientific rational behind current approaches.

Currently used confirmatory tests are not sufficient enough to establish the use of stem cells in drug discovery screening:

We will analyze stem cell based cardiomyocytes, which is one of the most "publicized" applications of stem cell based drug assay, as an example to understand whether stem cell derived products can be used in drug discovery screening assays. We would like to raise one question. Are we in a position to predict confidently that these cardiomyocytes, generated from stem cells have genomic stability? This means, stem cell derived cardiomyocytes do not posses genetic and somatic mutations, DNA polymorphism, chromosomal translocations, genomic instability due to polyploidy or anueploidy, miRNA polymorphism, metabolite variations and proteome polymorphism/modifications. These cellular or genetic changes can result from long-term cell culture system, molecules or genetic modifications that are used for the induction of differentiation and induced genetic rearrangements that are needed for the generation of stem cells, especially iPS cells, which may have some tumor cell properties. Mere confirmation of stem cell derived cardiomyocytes using DNA microarrays is not enough to establish the fact that stem cell derived cell types are genetically similar to normal cardiac cells/tissues. DNA microarray based approach does not address or identify unknown genes derived from alternative splicing/transposons, gene modifications and polymorphism, polyploidy or anueploidy, RNA modifications and epigenetic/mitochondrial DNA modifications. Therefore, the use of current DNA microarray based screening may be insufficient to establish the validity of stem cell derived products.

In addition to genes, miRNA, metabolites and proteins play significant role in genetic and physiological regulation in a particular cell type. A single change in post-translational modification in a protein can drastically change the cellular signaling process, which cannot be detected using DNA microarrays. This is also true with miRNAs and metabolites. The currently used stem cell derived products such as cardiomyocytes need to be established as true cardiac cells, both genetically and physiologically. This requires extensive scientific research. Until then, stem cell based assays for screening life threatening side effects such as cardiotoxicity should be carefully considered for drug development applications. There is a need for the development of reliable assays or technologies for the detection of genomic, proteomic, metabolomic, epigenetic and physiological instabilities in stem cell derived cell or tissue types.

Establishing a regulatory system for drug discovery assays will help in developing new drugs with fewer or no fatal side effects:

The development of new drugs based on stem cell derived assays, with very limited in-depth understanding of the system, needs to be reviewed diligently. How can we confirm that genetic or physiological instability of stem cell derived cardiomyocytes does not affect assay outcome, which is very critical? Can companies who develop such products, for example cardiomyocytes, guarantee that drugs developed using their stem cell technology do not have fatal cardiac side effects?. Under current system, anyone can aggressively market their products/technologies as a drug discovery tool based upon incomplete data or information because of the lack of regulation in this area. There are numerous examples where several products are marketed for drug discovery research without disclosing possible product limitations (see our earlier blog on cell based reporter assays). This is a major issue especially with proprietary/patented technologies owned by assay development companies or CROs. A very good example for this is reporter enzyme, homogeneous and cell based assays. Marketing proprietary technologies for all possible applications, without disclosing limitations, needs to be critically evaluated. So many public funded laboratories and facilities may also be using technologies, which were marketed to these customers with or without disclosing or foreseeing product limitations. It is important to note that consumers are protected from undesirable claims on pharmaceutical drugs, diagnostics and consumer products. Establishing an oversight regulatory system will help in checking product performance claims. Generating scientific and technical accountability monitoring system that starts from the bottom (e.g. reagent companies, CROs etc.) to the top (pharmaceutical companies) will help in generating robust pipeline of safer drugs. Any failure in a given drug should be scrutinized from the drug discovery research to development phase. Creating an oversight system is warranted especially for developing and marketing drug screening assays, similar to diagnostics products. This approach may slow-down development and application of drug discovery assays. However, in the long-run this will have significant positive impact on drug discovery research and development. This will help in selecting the right product for specific applications with complete understanding of limitations, which will help in developing alternative strategies. Finally, it is the choice of drug discovery researchers to address the need for a regulatory system for assays that are used in critical areas of drug discovery and development. These critical areas can be drug metabolism (ADME), cardiotoxicity, other organ/tissue specific toxicity, mutagenicity, and immunogenicity.

Categories: Stem Cells