Gene-editing pipeline takes off

@article{Mullard2020GeneeditingPT,
  title={Gene-editing pipeline takes off},
  author={Asher Mullard},
  journal={Nature Reviews Drug Discovery},
  year={2020},
  volume={19},
  pages={367-372}
}
  • Asher Mullard
  • Published 15 May 2020
  • Biology
  • Nature Reviews Drug Discovery
Clinical trials of genome-editing agents — including CRISPR–Cas9 editors, zinc finger nucleases and TALENs — are pushing ex vivo, immuno-oncology and in vivo treatment frontiers. Clinical trials of genome-editing agents — including CRISPR–Cas9 editors, zinc finger nucleases and TALENs — are pushing ex vivo, immuno-oncology and in vivo treatment frontiers. 

Therapeutic genome editing: regulatory horizons

An increasing number of genome-editing technologies are being developed and some of the key issues for future therapies using these technologies from a regulatory perspective are highlighted.

Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq+

It is demonstrated that inhibition of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) accumulates repair protein MRE11 at CRISPR-targeted sites, enabling high-sensitivity mapping of off-target sites to positions of MRE 11 binding using chromatin immunoprecipitation sequencing (ChIP-seq).

Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells

A clinical next generation sequencing workflow is employed to achieve high sequencing depth and detect ultra-low frequency variants across exons of genes associated with cancer, all exons, and genome wide and demonstrates that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.

Fluorescent in vivo editing reporter (FIVER): A novel multispectral reporter of in vivo genome editing

FIVER will broadly help expedite the development of therapeutic genome surgery for many genetic disorders and show the potential of FIVER for high-throughput unbiased screens, from small molecule modulators of genome editing outcomes in primary cells through to genome-wide in vivo CRISPR cancer screens.

Ultra-deep sequencing reveals no evidence of oncogenic mutations or enrichment by ex vivo CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells

Findings indicate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants and that even a single SNP outside the seed region of the gRNA protospacer is sufficient to eliminate Cas9 off-target activity with this method of delivery.

Leveraging DNA Damage Response Pathways to Enhance the Precision of CRISPR-Mediated Genome Editing

The study of the genetic mechanisms regulating large deletions that are generated upon repair of Cas9-induced DSBs is described, which has the potential to aid in the development of new strategies to limit their generation.

The Role of Recombinant AAV in Precise Genome Editing

This distinctive genome editing platform holds tremendous promise for the correction of disease-associated mutations without adding to the mutational burden.

Genome Editing among Bioethics and Regulatory Practices

Despite more than 50 years of discussion about the frontiers of genetics in human health and evolution, the debate about the bioethics and the regulatory practices of genome editing is still far from satisfactory answers.

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future.