The mission of the Center for Precision Animal Modeling (C-PAM) is to provide a national service to generate precision disease animal models for researchers and physicians working tirelessly to diagnose, treat, and study genetic diseases. Precision disease models carry the exact, patient-specific variants thought to underlie the diseases — using cells, worms, zebrafish, frogs, mice, and rats.
The University of Alabama at Birmingham, through funding provided by the National Institutes of Health (U54), has developed a Center for Precision Animal Modeling (C-PAM) led by Brad Yoder, Ph.D., Chair of the UAB Department of Cell, Developmental and Integrative Biology (CDIB) and Matt Might, Ph.D., Director of The Hugh Kaul Precision Medicine Institute.
Many persons with rare genetic disorders go without a diagnosis in spite of years of standard medical evaluations. Although genome sequencing now helps to identify the underlying cause for many, sequencing studies often end with the identification of a “variant of unknown significance” that leaves the diagnosis unresolved. Even those who do receive a specific diagnosis may be frustrated by the lack of therapeutic options. Disease models — including those based on cells, worms, zebrafish, frogs, mice, or rats — that reflect the molecular characteristics of a condition, can not only aid in better understanding of a disorder but can also be used to identify potential treatments.
These disease models are historically time-consuming and costly to create and often did not faithfully reflect a specific person’s genotype or phenotype. Until recently, the technology to create small and precise changes to the genome was not available, resulting in many models with large changes that completely disrupt a gene. While fruitful for the study of gene function in general, these models may not accurately replicate the phenotype seen in persons with specific genetic changes. New technologies, however, now make it possible to create models with the exact same genetic change as the human counterpart. The UAB Center for Precision Animal Models (C-PAM) brings together scientists and physicians to bridge the gap between affected persons and the most accurate models for their specific genetic conditions. These models will help elucidate how these disorders affect the body and potentially help find novel treatments for them.
Studying the effect of a genetic variant in a model makes it possible to confirm disease causation and link genotype to phenotype to support clinical diagnosis. Having a patient-specific variant in a model system also allows for the screening of therapeutics, which could lead to the discovery of targeted treatments for a person’s unique genetic condition.
Why the need?
With the rapid increase in the number of potential variants being identified through whole-genome sequencing technologies in persons with rare disorders, the challenge for geneticists now is to confirm that these variants are causative of the condition. This requires detailed assessment and annotation to separate the causative variants from those that are benign. This is a complex problem requiring interdisciplinary approaches, detailed bioinformatic analysis, the generation of informative animal models, and a concerted effort to evaluate the phenotypes caused by the variants.
How it works:
Accomplishing this goal is frequently beyond what an individual lab can easily or efficiently accomplish. C-PAM has assembled a team of scientists and clinicians with expertise in basic research, computational and data sciences, human genetics, clinical diagnosis, and animal model generation. The team has established a pipeline and solicits the research and clinical communities to nominate variants to be reviewed and prioritized for the production of a precision animal model. Our pipeline includes a review of patient information, bioinformatics analysis of the possible impact of the variants, an expert review of the ability to model the variant, and the availability of resources to study the model outside of C-PAM. Click here to submit a variant or be contacted for more information.
If selected, the C-PAM team will work closely with the submitting clinician or scientist to coordinate the initial evaluation of the model for relevance to the patient phenotype, and the model will be made available to the submitting researcher and to the research community at large.
C-PAM will leverage and organize our existing expertise to fulfill our vision to become a national resource for efficient and cost-effective analysis of patient-derived gene variants and to produce informative animal models to pursue disease mechanisms and targeted therapeutics.