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European Biopharmaceutical Review

Base Editing and Its Application to Cell and Gene Therapy

Propelled by the promise of faster, cheaper, and more accurate tools to selectively alter particular sequences in the genome, the past decade has seen the field of gene engineering dominated by CRISPR-Cas gene editing. For all of their ease and rapidity, conventional CRISPR-based approaches have a substantial flaw when it comes to gene editing for therapeutic use: unmodified Cas9 proteins result in DNA double strand breaks (DSB), which, although tolerable for a research tool, pose an additional safety concern for cell or gene therapy. The generation of unintended DNA strand breaks can be mitigated by various approaches, but the more recent invention of base editing offers another solution. Base editing uses an ‘attenuated’ nickase version of Cas9 linked to a deaminase enzyme and can achieve gene knockout or gene correction through the alteration of single bases without the formation of DNA DSBs. Base editing is a relatively nascent field and one that is still finding its niche within the wider gene editing and gene therapy arena. To better understand the current and future uses of base editors, it is better to focus on the development of these editors and on the emerging data that indicate how base editors might be used to treat genetic-based diseases with unmet clinical need.

The Basics of Base Editors

CRISPR-Cas-based gene editing relies on a short guide RNA sequence to direct the Cas enzyme to a specific DNA sequence where it introduces a DNA DSB. The cells intrinsic DNA repair pathways detect and repair this break, but for cells in culture, most DSBs are repaired using an imprecise mechanism that commonly leads to random insertions and deletions (indels) of DNA base pairs. It is the random nature of these repairs that can be used to efficiently disrupt or knockout gene transcription (1). However, the rate of single base changes as a result of the DNA repair is low (0.1-5%), making this approach inefficient for modifying single base pairs. Base editors are a derivation of the CRISPR-Cas system combining a modified version of the Cas enzyme only capable of generating a nick on one strand of the DNA, directly linked to a deaminase enzyme. They still make use of short guide RNA sequences to direct the complex to the target loci on the DNA, where the Cas enzyme nicks the non-target strand to promote the deamination of single base pairs of DNA.

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Dr Ceri Wiggins is an R&D Manager at Horizon Discovery. Upon joining the company in 2011, she played a significant role in establishing the screening services that are now a key offering in the company’s portfolio. Today, Ceri leads a scientific team focused on the development and commercialisation of a novel base editing platform, as well as supporting multiple client, CRISPR-based, target validation programmes. Before joining Horizon, Ceri worked at the MRC National Institute for Medical Research in London under Dr Steve Ley, having gained her doctorate at the University of Cambridge, UK.
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