Applications
Precisely defined diseased vs. normal ‘isogenic’ cell-lines can be applied to impact many aspects of the drug discovery process including: target identification, target validation , target economic catagorisation; drug MOA, therapeutic window and patient responsiveness and; clinical trial design.
Target Identification and Validation
Many disease genes, especially in cancer, are not directly drugable. Therefore, there is a need to search for downstream targets that can be targeted and also have an influence on the disease.
Stable and definitive tumour vs. normal isogenic models allow the use of high-throughput screening tools, such as microarrays and functional RNAi’s to identify novel target-candidates that selectively impact a chosen genotype.
Moreover, by using isogenic cell-lines the user will inherently understand if altering that gene has selective effects on a disease vs. normal cell type - thus feeding the drug discovery process with candidates that have higher chance of success.
GENESIS can also be used to provide a final validation step for any triaged candidates by directly knocking out their function in the genome.
Understanding Your Target
Using GENESIS, highly targeted alterations can be made in genes of therapeutic interest.
In this example, the kinase domain is mutated to remove only the catalytic activity of cMET.
e.g., Kinase-Dead KI of cMET – Arena et al, PNAS 2007
The below data-sets illustrates the typical phenotype and drug responses of this targeted kinase-dead KO of cMET.
cMET Cell Growth Effects - Arena et al, PNAS 2007
Kinase dead cMET does not affect cell-growth under basal in vitro conditions, but abrogates the migratory effect of HGF – the growth factor that binds cMET.
A targeted cMET inhibitor effects - Arena et al, PNAS 2007
A targeted cMET inhibitor, however does restrict cell growth in vitro – indicating significant off-target effects for this compound.
Kinase dead cMET effect on growth of tumours in vivo - Arena et al, PNAS 2007
Kinase dead cMET does have a significant effect, however, on the growth of tumours in vivo.
Relevant data-sets are available for each application and can be shared under confidential disclosure agreement. Please write to info@horizondiscovery.com for details
Horizon Offering
- Horizon Discovery has a wide range of isogenic models available for immediate licensing or purchasing (Learn more) and; can also develop custom isogenic models or screen drug candidates against your specific gene target (Learn more)
References
- Arena et al, PNAS, 2007
- Horizon Discovery Ltd. Technical Presentation (Download (6.95MB))