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Feb. 24, 2017 Research Highlight Biology

Non-dividing and conquered

A method for targeted insertion of DNA into non-dividing cells helped partially restore vision to blind rats

Image of neurons in mouse brain Figure 1: A mouse brain showing cell nuclei (blue) and genome-edited neurons (green). © 2017 Salk Institute

Faulty genes responsible for disease can now be replaced with healthy versions in any cell type in the body, thanks to a new gene-editing technique developed by a team that includes RIKEN researchers1. In the future, this development is expected to make many incurable diseases treatable by gene replacement therapy.

The CRISPR-Cas9 gene-editing system holds great therapeutic potential because it allows scientists to modify the genome at specific locations. However, the ability to modify the genome in this way has historically been most effective in dividing cells, such as those found in the liver and bone marrow. Unfortunately, the vast majority of the body’s cells—including those in the eye, brain, pancreas and heart—are non-dividing.

To develop a more versatile gene-editing platform, an international team, which included Yuji Tsunekawa and Fumio Matsuzaki from the RIKEN Center for Developmental Biology, focused on a mechanism for repairing DNA known as non-homologous end joining. This molecular repair system normally fixes broken strands of the genome in both dividing and non-dividing cells by reconnecting the original strand ends.

The researchers adapted the cell’s natural non-homologous end-joining machinery to work in tandem with introduced CRISPR-Cas9 tools to insert desired DNA into targeted positions. This strategy allowed them to deliver genetic instructions to human neurons in a laboratory dish and to the brains of adult mice (Fig. 1).

“We have developed the first method that can efficiently target the genome of non-dividing cells both in a culture dish and in the body,” comments Tsunekawa.

To demonstrate the potential of this new application of CRISPR-Cas9 for gene-replacement therapy, the researchers tested the system in a rat model of retinitis pigmentosa—a major incurable cause of blindness that afflicts one person in every 3,000–4,000 people in Japan. They delivered a functional copy of one of the genes damaged in people with this vision disorder to the eyes of three-week-old rats. One month later, they documented gene expression in the rats’ retinas. In addition, the animals showed improved responses on light-sensitive eye tests.

These are still early days since many improvements are needed to ensure the safety and efficacy of the method. “It will take a long time before this gets to clinical testing,” Tsunekawa notes. But the researchers are very excited about the development. “In principle, most human diseases that are caused by a single gene defect could be treated by this method,” says Tsunekawa.

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References

  • 1. Suzuki, K., Tsunekawa, Y., Hernandez-Benitez, R., Wu, J., Zhu, J., Kim, E. J., Hatanaka, F., Yamamoto, M., Araoka, T., Li, Z. et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144–149 (2016). doi: 10.1038/nature20565

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