To enable understanding of the etiology of a disease and the variation of the effects of drugs in a population.

1. Aim:
To enable understanding of the etiology of a disease and the variation of the effects of drugs in a
population.
Short description:
The unexpected side-effects that suddenly emerge in late phase clinical trials are costly and very
difficult to protect against.
A suggested way to address at least some of the problems is to phenotypically screen the drug in
question against a large set of primary cells that cover a large segment of the target population. A
suitable type of cells is the Human Umbilical Vein Endothelial Cell, HUVECs. HUVECs can be
passaged up to 8 times without losing the responsiveness to stimuli, such as cytokines and growth
factors and can be harvested from single individuals.
By using a pre-determined set of phenotypic assays covering a space in the transcriptome/proteome
of relevant size, it would be possible to see if the drug in question has a different type of activity in
any of the tested individual donor HUVECs. The breadth of biology that the selected assays cover
will be determining the possibility to identify differences in reactions to the drug. The identified
differences will cast light on previously unknown individual pharmacokinetics that can
subsequently be included as screening criteria in later projects.
To validate the hypothesis it would be ideal to acquire live primary cells from a set of patients that
has experienced defined and severe reactions to a drug. The set of cells would be queried against a
negative set of cells from patients with similar medical history but lacking adverse reactions to the
drug in question and thereby enable understanding of the etiology of the disease. Depending on the
actual disease in question and the quality of the data from the drug development, the needed size of
the patient cohort will differ.
If the hypothesis can be successfully validated, the method can be developed to screen large
population segments even before initiating a clinical trial. The suggested size of the cell collection
depends on the regulations from FDA regarding accepted frequency of side effects, i.e. if a
frequency of 1:10,000 is accepted then the collection of cells has to reflect this to a certain statistical
certainty. An aspect of the findings is the potential to generate a pre-defined set of assays that can
be used to test a patient before exposing to the drug in question.
The closest comparison is to use SNPs for drug specific variations.