Build or Buy: Animal Model Licensing in the Age of CRISPR

Megan M. MacBride, PhD
Tuesday, August 20th, 2019
Genetically modified mice and rats have been around for decades. But, until recently, the cost and effort involved in generating genetically engineered models (GEMs) using the available technologies were relatively high. This meant that requesting access to a model described in the literature was the fastest way to start a research project with that reagent, even if the material transfer agreement (MTA) or license process delayed transfer of the model.

But that may no longer be the case now that CRISPR gene editing can speed up generation of a GEM. For a simple knockout mouse, the original technology of homologous recombination in embryonic stem cells takes about 38 weeks to generate heterozygous germline-transmitted mice. With the CRISPR/Cas9 system, heterozygous germline-transmitted mice can be generated in as little as 24 weeks.

What is an MTA?

Material transfer agreements are legally-binding documents which control how reagents such as cell lines and GEMs are shared and used.

Universities commonly use MTAs to govern transfer of GEMs from one investigator to another at a different institution. These agreements usually limit the recipient's use of the material to only not-for-profit research and prohibit further distribution of the material to third parties. Universities may make GEMs available to pharmaceutical and biotech companies under MTAs, but more commonly they license those materials out under fee-bearing agreements.

Licensing Animal Models Can Be Costly and Time-Consuming

When a for-profit company requests access to a university's GEM for drug discovery purposes, the university technology transfer office begins negotiations with the company. These negotiations can take many months, as the parties engage in detailed discussions of terms such as field of use (the types of research the GEM can be used in), indemnification and license fees.

Depending on the model, license fees can range from $10,000-$1,000,000.

Unfortunately, sometimes the two parties are not able to come to terms, resulting in wasted months of effort and no access to a reagent the company needs to perform important research.

CRISPR Makes Designing Your Own Model Easier (Sometimes)

For pharmaceutical and biotech companies, speed is often the most important factor. When licensing a GEM model from an academic institution is at best a three-month process, and at worst impossible, building a model starts to look much more attractive.

Time to generate a knockout mouse model with ES Cell-Based Technology and with CRISPR Gene Editing in Zygotes For knockouts and simple knock-ins, more companies are choosing to recreate published models using CRISPR/Cas9-mediated gene editing rather than deal with the uncertainty in cost and timeline inherent in the licensing process. Although there is some risk that a remade model won't recapitulate previously published results, perhaps due to differences in genetic background or other factors, this risk may be more palatable than the risk of not coming to a successful agreement with a university to gain access to a critical research tool.

Off-target mutations in models made using CRISPR/Cas9 gene editing are also a risk, but this risk can be minimized through appropriate off-target analysis and careful management of subsequent breeding steps.

Furthermore, recreating the model may offer additional benefits compared to licensing from an academic institution. Many licensing agreements have significant restrictions, which can include restrictions on field of use for the animal model. These restrictions may limit the types of research in which a company may use the model.

Recreating a model may provide a company with broader use rights. If there is not a patent on the model itself, the option to remake a published model is available.

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