How animal models will advance precision medicine

By Melissa Fassbender

- Last updated on GMT

The Precision Medicine Initiative (PMI) was announced in President Obama’s 2015 State of the Union Address. (Image: iStock/lculig)
The Precision Medicine Initiative (PMI) was announced in President Obama’s 2015 State of the Union Address. (Image: iStock/lculig)

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A year into the program, animal models of human disease could augment NIH’s Precision Medicine Initiative, say researchers.

In his editorial published​ in Science Translational Medicine today, Kent Lloyd, a professor at the Department of Surgery, School of Medicine, and the Director of the Mouse Biology Program at the University of California, said that animal-based studies will be essential for precision medicine.

As Lloyd explained, the PMI will use an individual’s “omics” profile (genomics, proteomics, metabolomics) and biomarkers of disease within an environmental context, incorporating lifestyle and behaviors to define a molecular diagnosis, inform targeted therapeutics, predict treatment outcomes, and design reliable preventative strategies. 

Animal models can be used in all of these areas,” ​Lloyd told, “including identifying putative disease genes, recreating and testing potential disease-causing alleles observed in patients, exposing such animal models to relevant environmental conditions, testing and validating targeted therapeutics, predicting treatment outcomes, and testing prevention strategies​.”

According to Lloyd, the PMI will emphasis screening genomic sequences to expose disease associated variants. “However, the number of variants of known or highly suspected pathogenicity is reaching a plateau, the numbers of variants of unknown significance (VUS) is and will continue to increase exponentially​,” he explained.

As such, to determine the risks of VUS using statistical evaluation of patient data only, “will take a very, very long time​,” said Lloyd – if it will be achievable at all. However, animal models can be used to prioritize VUS.

For example, NIH’s Knockout Mouse Production and Phenotyping (KOMP2) project in collaboration with the International Mouse Phenotyping Consortium (IMPC), are currently identifying likely disease genes using comprehensive phenotyping across multiple body systems in mice with specific gene knockouts. 

Thus, VUS can begin to be prioritized as possibly disease causing if they are found to occur in genes in knockout mice that exhibit a disease-like phenotype​,” said Lloyd. “These gene-prioritized VUS can then be recapitulated in mice that can be tested for the disease phenotype​.”

Lloyd noted that he only mentions mice here as an example, but that numerous animal models, such as zebra fish, rats, pigs, C elegans, Drosophilla, etc., are also applicable in the appropriate context.

Genetically-engineered/genome edited animal models will generate new knowledge about gene function that we don’t know now​,” added Lloyd. “This new knowledge could come quickly for rare, single inherited genetic defects in people.​”

And of the approximate 7,000 clinically-described inherited diseases, Lloyd said only half have a known genetic basis. “That gap could be closed rapidly using animal models​,” he added, “and this knowledge of individual gene function is the basis upon which precision medicine will advance​.”

Lloyd said the next step will be addressing more common, but more complex diseases, which are multigenic. “Creation of animal models with these multifactorial associations will also catalyze the impact of precision medicine on the broader population​,” he explained.

Over the next five years Lloyd predicts that the number and type of animal models should grow dramatically over the next 5 years. “And if all of them undergo comprehensive phenotyping, then the knowledge gap faced today by precision medicine should begin to close​,” he said.

The ability to quickly and simply design high-fidelity genome edits in numerous animal species in a reliable manner using CRISPR/Cas9 is transforming the application of research animals as models of human disease​.”

Related topics Clinical Development Preclinical

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