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GENOME EDITING

Nanoparticles for CRISPR–Cas9 delivery

Nature Biomedical Engineering volume 1, pages 854–855 (2017)Cite this article

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The DNA mutation that causes Duchenne muscular dystrophy in mice can be corrected, with minimal off-target effects, by gold nanoparticles carrying the CRISPR components.

From zinc-finger and transcription activator-like effector nucleases to CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR associated protein 9), the ability to repair genetic diseases at the DNA level has been a tantalizing goal1,2. The motivation is obvious: a wide range of diseases with genetic aetiology currently have no cure, and the standard of care is based on managing symptoms rather than addressing the root cause. In January 2016, three papers published in Science demonstrated how CRISPR–Cas9-mediated correction of a defective dystrophin gene ameliorated the pathology in a mouse model of Duchenne muscular dystrophy (DMD)3,4,5. The three studies used a technique known as exon skipping, in which paired Cas9 guide RNAs (gRNAs) were designed to target either side of a mutation-harbouring exon; as both sites were cleaved simultaneously, the exon was excised from the genome and the ends were joined by an endogenous DNA repair mechanism known as non-homologous end joining. In this process, the mutation is not repaired per se, but rather ‘skipped over’, resulting in a truncated protein that nevertheless retains some biological function. A major limitation of these trials was the use of adeno-associated virus (AAV) as vectors for the in vivo delivery of the CRISPR machinery to cells. Despite AAV-mediated CRISPR delivery resulting in a strong, robust expression of Cas9 and in high levels of editing efficiency, viral vectors have several drawbacks as a clinical-grade therapeutic. From a regulatory perspective, viral therapeutics have historically struggled to obtain approval by the Food and Drug Administration, with only a handful of applications having received approval so far. By comparison, the number of approved protein therapeutics, already in the hundreds, is exponentially growing. The development of better tools to deliver CRISPR proteins directly would thus avoid the need for viral vectors. Reporting in Nature Biomedical Engineering, Niren Murthy, Irina Conboy and colleagues now show that functionalized gold nanoparticles can deliver Cas9 and donor DNA both in vitro and in a mouse model of DMD6. The approach represents a significant step towards realizing non-viral CRISPR therapeutics.

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Fig. 1: Genome editing via nanoparticle-mediated delivery of the CRISPR–Cas9 machinery.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Tufts University, Medford, MA, USA

    Zachary Glass, Yamin Li & Qiaobing Xu

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  1. Zachary Glass
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  2. Yamin Li
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  3. Qiaobing Xu
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Correspondence to Qiaobing Xu.

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Glass, Z., Li, Y. & Xu, Q. Nanoparticles for CRISPR–Cas9 delivery. Nat Biomed Eng 1, 854–855 (2017). https://doi.org/10.1038/s41551-017-0158-x

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