Editors' ChoiceGenomics

Monkeying Around with the Genome

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Science Translational Medicine  26 Mar 2014:
Vol. 6, Issue 229, pp. 229ec56
DOI: 10.1126/scitranslmed.3009020

The ability to accurately model human disease in the laboratory limits the development and translation of new therapeutics. Major advances such as precise gene modification in mice and patient-specific induced pluripotent stem cell lines have transformed biomedical research, ultimately leading to Nobel Prizes in 2007 and 2012. However, these technologies cannot recapitulate the whole-organism physiology of humans and as such are restricted in their ability to model disease and predict efficacy of new therapeutics. With the first demonstration of human disease–relevant targeted gene editing in monkeys, Liu et al. offer a new approach to more faithfully model human diseases.

In this study, the authors set out to generate gene-modified cynomolgus and rhesus monkeys—relatively accessible laboratory models with similar physiology to humans. Although transgenic monkeys had been generated previously by using viral delivery methods, precise mutation of known disease loci in the genome of whole primates had not been achieved. Liu et al. used the TALEN gene-editing technology to target the monkey MECP2 gene, a locus known to underlie the X-linked human neurodevelopmental disorder Rett syndrome. The TALEN system uses customized DNA-binding proteins fused to a DNA nuclease, allowing for targeting of any location in the genome. TALEN pairs induce a double-stranded break at the target locus that often results in indel mutations and perturbation (“knockout”) of target gene function. The authors’ major advance was the successful gestation of three rhesus and eight cynomolgus fetuses that had been injected with MECP2-targeted TALEN pairs at the zygote stage. None of the transferred rhesus fetuses survived to term; however, analysis of two of the miscarriages showed clear evidence of MECP2 mutations in the fetal tissue. As these fetuses were both male, the preterm lethality is consistent with the X-linked lethality seen in male Rett syndrome patients. One female cynomolgus infant was born that showed successful mutagenesis of the MECP2 locus in multiple somatic tissues; however, it is too early to know whether relevant disease phenotypes will manifest.

This study provides a major advance in the quest to generate faithful primate models of human disease. However, more work is needed to understand the reliability, efficiency, and utility of this technique, especially given the time, cost, and ethical challenges of nonhuman primate research.

H. Liu et al., TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. Cell Stem Cell 14, 323–328 (2014). [Abstract]

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