ExpressMODEL® Embryonic Stem Cell Platform

Traditional mouse model generation, when performed using gene targeting in embryonic stem cells (ESCs), can take a significant amount of time – with typical timelines required for the production of F1 heterozygotes often reaching 10-12 months. In addition to this, two to three generations of breeding can be required after F1 heterozygotes are available. First to expand the number of heterozygotes available, and then to produce an initial cohort of homozygous mice which can be used for experiments.

Variability can also complicate this process, and risk delays to the timeline. It can occur at several points during model generation workflow, though two are crucial to maintaining timelines. The first of these is chimera production. When cells from a validated ESC clone are injected into a wild-type host embryo, there is always uncertainty regarding the extent to which they will contribute to the adult (chimeric) mouse. In turn, and if their contribution is relatively low, this can affect the efficiency of germline transmission. This is the second crucial point – transmission of the targeted allele through the germline, for the production of F1 heterozygotes. As this is traditionally accomplished through natural mating, delays can occur if individual chimeras display varied levels of reproductive performance.

The ExpressMODEL® Platform for ESC based custom model generation projects is a novel approach developed by Taconic Biosciences, which not only helps to mitigate the risks described above but significantly reduces overall timelines. Importantly, this is done without making any compromise to quality, as there is no change to the validation work performed after both vector construction and ESC targeting.

Instead, and by addressing the first point above (chimera production), ExpressMODEL® allows for the reliable production and identification of male chimeric mice with high ESC contribution to the germline. This allows for efficient germline transmission, which can be problematic in traditional mouse model generation (or without these analyses). By addressing the second point above (F1 heterozygote production), ExpressMODEL® allows for reliable and scaled generation of higher deliverables (≥ 20-50 F1 heterozygotes) via in vitro fertilization (IVF), without any addition to the model generation timeline. In turn, this allows for the immediate production of homozygous mice in the next generation. Bypassing colony expansion, this saves 3-4 months on overall project timelines. 

The use of IVF also allows for the production of F1 heterozygotes at a defined health standard. Since these mice can be immediately transferred to one of Taconic's Isolated Barrier Units, large-scale cohort production can begin immediately, and without any delay required for shipment to another provider, additional testing, or quarantine.