The delivery challenge: fulfilling the promise of therapeutic genome editing

doi:10.1038/s41587-020-0565-5

Review

. 2020 Jul;38(7):845-855.

doi: 10.1038/s41587-020-0565-5. Epub 2020 Jun 29.

The delivery challenge: fulfilling the promise of therapeutic genome editing

Joost van Haasteren^#¹, Jie Li^#^{2

3}, Olivia J Scheideler^#², Niren Murthy^{4

5

6}, David V Schaffer^{7

8

9

10

11

12}

Affiliations

¹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
² Department of Bioengineering, University of California, Berkeley, CA, USA.
³ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA.
⁴ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁵ Department of Bioengineering, University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁶ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁷ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
⁸ Department of Bioengineering, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
⁹ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹⁰ Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹¹ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹² Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.

^# Contributed equally.

PMID: 32601435
DOI: 10.1038/s41587-020-0565-5

Review

The delivery challenge: fulfilling the promise of therapeutic genome editing

Joost van Haasteren et al. Nat Biotechnol. 2020 Jul.

. 2020 Jul;38(7):845-855.

doi: 10.1038/s41587-020-0565-5. Epub 2020 Jun 29.

Authors

Joost van Haasteren^#¹, Jie Li^#^{2

3}, Olivia J Scheideler^#², Niren Murthy^{4

5

6}, David V Schaffer^{7

8

9

10

11

12}

Affiliations

¹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
² Department of Bioengineering, University of California, Berkeley, CA, USA.
³ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA.
⁴ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁵ Department of Bioengineering, University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁶ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA. nmurthy@berkeley.edu.
⁷ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
⁸ Department of Bioengineering, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
⁹ Innovative Genomics Institute (IGI), University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹⁰ Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹¹ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.
¹² Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA. schaffer@berkeley.edu.

^# Contributed equally.

PMID: 32601435
DOI: 10.1038/s41587-020-0565-5

Abstract

Genome editing has the potential to treat an extensive range of incurable monogenic and complex diseases. In particular, advances in sequence-specific nuclease technologies have dramatically accelerated the development of therapeutic genome editing strategies that are based on either the knockout of disease-causing genes or the repair of endogenous mutated genes. These technologies are progressing into human clinical trials. However, challenges remain before the therapeutic potential of genome editing can be fully realized. Delivery technologies that have serendipitously been developed over the past couple decades in the protein and nucleic acid delivery fields have been crucial to genome editing success to date, including adeno-associated viral and lentiviral vectors for gene therapy and lipid nanoparticle and other non-viral vectors for nucleic acid and protein delivery. However, the efficiency and tissue targeting capabilities of these vehicles must be further improved. In addition, the genome editing enzymes themselves need to be optimized, and challenges regarding their editing efficiency, specificity and immunogenicity must be addressed. Emerging protein engineering and synthetic chemistry approaches can offer solutions and enable the development of safe and efficacious clinical genome editing.

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References

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[1] Boycott, K. M., Vanstone, M. R., Bulman, D. E. & MacKenzie, A. E. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14, 681–691 (2013). - PubMed - DOI

[2] Boycott, K. M., Vanstone, M. R., Bulman, D. E. & MacKenzie, A. E. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14, 681–691 (2013). - PubMed - DOI

[3] Nathwani, A. C. et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371, 1994–2004 (2014). - PubMed - PMC - DOI

[4] Nathwani, A. C. et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371, 1994–2004 (2014). - PubMed - PMC - DOI

[5] Hoggatt, J. Gene therapy for “bubble boy” disease. Cell 166, 263 (2016). - DOI - PubMed

[6] Hoggatt, J. Gene therapy for “bubble boy” disease. Cell 166, 263 (2016). - DOI - PubMed

[7] Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008). - PubMed - PMC - DOI

[8] Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008). - PubMed - PMC - DOI

[9] Choo, K. H., Gould, K. G., Rees, D. J. & Brownlee, G. G. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 299, 178–180 (1982). - PubMed - DOI

[10] Choo, K. H., Gould, K. G., Rees, D. J. & Brownlee, G. G. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 299, 178–180 (1982). - PubMed - DOI

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The delivery challenge: fulfilling the promise of therapeutic genome editing

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The delivery challenge: fulfilling the promise of therapeutic genome editing

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