Editors' ChoiceGENE EDITING

Magnets make target cells more attractive to CRISPR

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Science Translational Medicine  05 Dec 2018:
Vol. 10, Issue 470, eaaw0520
DOI: 10.1126/scitranslmed.aaw0520


Local CRISPR-Cas9–mediated genome editing using magnetic nanoparticles complexed with recombinant baculoviral vectors minimizes genotoxicity.

Since the creation of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene editing technology, there has been increasing interest in fine-tuning control of the tool, including the selective and temporal activation of the CRISPR-Cas9 system in desired tissues. In a recent study, Zhu et al. used iron oxide nanoparticles to magnetically guide a baculoviral vector (BV), creating a magnetic nanoparticle-BV hybrid (MNP-BV) for spatial control over gene editing.

A previous challenge for BV application in CRISPR-Cas9 delivery was serum inactivation of the virus by complement proteins; however, MNP-BVs exposed to a magnetic field overcame this inactivation, resulting in a fivefold increase in transgene expression compared with BVs alone or MNP-BVs without a magnetic field. This finding was conserved in multiple cell lines and found to use an uptake mechanism involving macropinocytosis through induced actin filament polymerization.

The authors sought to demonstrate that a major CRISPR-Cas9 limitation—spatial control over gene editing—could be overcome using MNP-BVs. Cells incubated with MNP-BVs encoding green fluorescent protein showed selective uptake only when exposed to a magnet. After intratumoral injections in mice, MNP-BVs encoding luciferase led to a significant increase in luciferase expression in tumors but not in surrounding tissue. In healthy mice, the authors demonstrated organ-specific gene modification in the liver when a magnet was placed by the liver, without off-site modification in adjacent or distant organs. In tumor-bearing mice, next-generation sequencing revealed that systemically administered MNP-BV–mediated vascular endothelial growth factor receptor 2 (Vegfr2) gene modification occurred only in tumors, although at lower indel rates than intratumoral administration.

When applied to diseases like solid tumors, however, MNP-BV penetration throughout the tumor was still limited and heterogeneous—even in the presence of a magnetic field. The mouse is also a small species relative to the applied magnetic field (1.4 T), and when targeting the spleen, the authors saw off-site gene modification in the liver. Determining whether the MNP-driven localization of the BV-CRISPR gene editing tool retains site specificity when administered systemically in large animals, including humans, will require evaluation of this technology in large species with coil-based and nonblock magnets of varying strengths and positions, and in combination with different routes of MNP-BV administration. Surface modifications could also be added to the MNP platform to increase tissue penetration and further enhance the site specificity and homogeneity of CRISPR-Cas9 editing. Therefore, although this work provides one important step toward spatial control over CRISPR-Cas9 gene editing, several considerations still need to be addressed.

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