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Precision Disease Modeling

The era of personalized medicine is being realized through the testing of therapies on animal avatars.

Highly accurate research tools such as the CRISPR-Cas9 genome editing tool enable researchers to pinpoint, edit, or deactivate specific genes to create animal models with the exact same disease-implicated genetic sequences as a given individual. Different therapies can be tested on these models, to find the one that triggers the optimal response in that particular patient. The process of establishing a line of genetically-customized avatars could take a year or more with the older gene-editing technology; CRISPR speeds up the timeline dramatically.  

This approach is called precision disease modeling, and it’s a key development in the emerging practice of personalized medicine. The 2013 Division of Comparative Medicine Symposium on Animal Models and Personalized Medicine highlighted the need for coordinated research projects to facilitate knowledge and resource sharing in precision disease modeling. Three U54 grants were subsequently awarded by ORIP, funding pilot centers where researchers across disciplines collaborate to link advances in animal genomics and technology with personalized medicine efforts in human subjects:

  • The pilot center at Memorial Sloan-Kettering Cancer Center studies the genetic mechanisms of premature aging syndromes and colorectal cancers; it also seeks to develop precision treatment strategies for patients with acute leukemia.
  • The JAX Center for Precision Genetics is developing mouse models to support precision disease modeling.
  • The Mount Sinai Pilot Center for Precision Disease Modeling, seeks to leverage the fruit fly (a widely used model for genetic research), stem cells, and xenografts (human tissue transplanted into mice) to provide a “fly-to-bedside” approach to the study of colorectal cancer and rare genetic diseases such as Noonan syndrome (a genetic condition that can lead to unusual facial features, short stature, and the potential to develop bleeding, skeletal, and heart problems).

“We are working in parallel across the three precision centers to develop new treatments,” says Ross Cagan, Ph.D., who directs the work at the Mount Sinai Pilot Center. “This is a unique opportunity to integrate different approaches to address what have proven to be difficult diseases to treat.”

The Mount Sinai Center uses precision animal modeling in flies and stem cells to study mechanisms that lead children with Noonan syndrome to develop life-threatening enlarged hearts. “We put specific mutations in the fly that match a specific kid,” says Dr. Cagan.

Project co-leader Bruce Gelb, M.D., creates the same mutations in stem cells, to build a customized models of the child’s heart. Therapies are developed using the fly avatar models; those that work are then tested on the personalized heart models built from the stem cells. Promising therapies from these pre-clinical experiments are further tested and refined in clinical studies with human subjects.

Dr. Cagan notes that the ORIP funding allows scientists to tackle rare genetic diseases that get less attention because there is less demand for the therapies to treat them. “ORIP has been central to our ability to develop and promote precision animal models,” he says. “By establishing a U54 grant to support our efforts, ORIP has given my colleagues and me an opportunity to push our ideas much further toward directly helping patients.”

Related reading:

Das, T. K., & Cagan, R. L. (2013). A Drosophila approach to thyroid cancer therapeutics. Drug Discovery Today: Technologies 10 (1), e65–e71. doi:  10.1016/j.ddtec.2012.09.004.