Emerging Use of Mouse “Avatars” Accelerates Precision Medicine

by Tim Bonfield


One of the most exciting trends in genomics has been the emergence of the human-to-mouse-to-human approach to diagnosing and treating rare conditions.

Until very recently, the cost and complexity of conducting whole genome and whole exome sequencing made these tools impractical for use in patient care. Now these research devices are evolving into clinical life-savers.

Kenneth Kaufman, PhD.

Custom-built mice: Gene sequencing and editing technology has become so quick that clinician-scientists such as Kenneth Kaufman, PhD, can use mouse avatars to refine diagnoses and test-drive precision treatment plans.

At Cincinnati Children’s, Kenneth Kaufman, PhD, is pursuing a two-track genomic strategy to do battle against the rare lung disease hereditary pulmonary alveolar proteinosis (hPAP).

One track reflects an accelerated but traditional research model: gather samples from people diagnosed with the condition. Conduct genetic analysis to generate a list of suspicious DNA variations. Conduct further tests, usually in animal models, to confirm which polymorphisms are most likely to be disease-related. Publish a paper detailing new therapeutic targets.

Under this model, the hoped-for result would be that a future generation of children might benefit from faster technology speeding up the process of discovering disease-related variants that eventually could lead to new medications.

The other track, however, is far more individualized. Kaufman and colleagues in the Transgenic Animal and Genome Editing (TAGE) core laboratory at Cincinnati Children’s are creating highly custom mouse models that reflect the genomic disease profiles of specific children. The technology has become so quick that custom lines of humanized mice can be generated in as little as three months. These mouse avatars can allow clinician-scientists to explore various possible treatments without risk to the patient, then recommend the most effective option for actual use.

The improving speed of this process has made the avatar approach an increasingly attractive option when treating children with rare, severe, high-cost conditions. At Cincinnati Children’s, mouse avatars already play important roles in treating children with relapsed cancers and in research related to mitochondrial diseases. This is precision medicine in action.

Professional Education Opportunities

Advancing genomic knowledge is an integral part of our mission. The Center for Pediatric Genomics offers a variety of seminars for health professionals. Cincinnati Children's also integrates genomics into several fellowship, degree and professional certification programs. Learn more.


Kaufman’s work involves studying a Kuwaiti family that includes a sister and a brother who share a rare gene deletion associated with hPAP, but surprisingly, only the girl has developed the disease. Whole-exome sequencing has revealed that the girl possesses a second polymorphism, in a gene specifically expressed in lung tissue, that appears to explain why she developed the disease but her brother did not.

As the team continues its work, it may someday be possible to transplant edited versions of the girl’s own lung stem cells so that they lack the second polymorphism, Kaufman says. Such a result may never lead to a blockbuster drug, but the effort could close the loop for a child like this, giving her a chance to grow up without enduring whole-lung lavage treatments, the primary therapy for her condition.


The outcome in this case remains uncertain. But just the possibility of playing a direct role in saving a child’s life, even if they never meet face-to-face, inspires Kaufman.

“When we conduct whole exome sequencing, most of the polymorphisms we find have no causative relationship with the disease. Even when we find an association, in most cases, it does not mean a person is certain to develop the disease. It only means that the risk is elevated,” he says. “But sometimes we can find the culprit. And when that leads to an effective therapy, it can be a very rewarding feeling.”