Base editing: All your questions answered

Therapeutic developers are on the pinnacle of revolutionizing cell therapies with cutting-edge technologies for editing the genome. However, classical genome editing techniques can suffer from questionable safety profiles when utilized for the simultaneous modification of multiple loci. As an alternative, base editing technology may provide the cell therapy community with a safer solution.

In this on-demand SelectScience webinar, Dr. John Lambourne, R&D manager in the therapeutics applications arm of the Horizon Discovery Pin-point™ base editing team, covers the advantages inherent in utilizing base editing technology and the possible impact this could have on the development of cell therapies. Lambourne also presents some initial data generated during the development of Horizon's Pin-point™ base editing system and describes how organizations can access the system.

Read on for highlights of the live Q&A session or register to watch the webinar at any time that suits you.

Q: What is the probability of off-targeting using base editing?

JL: Based on off-targets as a whole, when you think about guide-specific off-targets then probabilistically this is going to be a similar factor to what you observe with CRISPR wildtype off-targets. Considering editing windows in relation to base editing specifically, the factor changes slightly. We would typically expect there to be a reduced chance of guide-specific off-targets in relation to base editing, but it is difficult to give an exact probability.

Q: What is the benefit of base editing compared to prime editing?

JL: Prime editing is quite exciting, and we’ve seen the impact it has had over the past 12 months – it’s made quite a splash in the press. Regarding how base editing and prime editing compare, they are quite technically different in terms of their mechanistic processes, but they could be seen as complementary when it comes to the cell and gene therapy space. Both have strengths and weaknesses in their use against a wide range of diseases and so they may potentially help each other, not in direct application, but in their suitability for different situations. I personally see them as quite complementary.

Q: Base editing looks like it has good potential as a cell or gene therapy, but what do you think is the biggest challenge in this field of work?

JL: In the field of cell and gene therapy as a whole, the way you deliver your components or your reagents for any given disease is always going to be a bottleneck. In the case of gene therapies, in vivo application probably poses the biggest challenge. Outside of delivery, safety is always a concern – you don’t want to create disease with your cure for disease.

Q: Do you see other applications for base editing outside cell and gene therapy?

JL: Absolutely. In some respects, the world is the limit in terms of how you apply base editing. The ability to change DNA precisely and with control in a living cell is very powerful. For example, when talking about model generation screening and applications of that nature, which are outside of the human body and the cell and gene therapy space, base editing has a lot of potential.

Q: The FDA has only just approved CRISPR editing for therapies. Do you anticipate any extra considerations for base editing?

JL: Base editing does have extra considerations, but generally speaking these are relatively minor compared to the advantages it offers. The safety profile is inevitably going to be different but at the same time, you are circumventing quite a number of other potential hurdles on the safety side of things.

Ultimately, these considerations are things we are interested in driving forwards to understand the safety of the systems. As an example, within the literature in the past 8-12 months, there has been a lot of work looking at RNA off-targets and the question of whether these are problematic or not. It really depends on how you are applying the system. In most scenarios, you’re going to be applying your system transiently, and when you come to therapies, you are mostly interested in what point you hit steady-state, the point at which you are applying the therapy into the host. If by this point they are not problematic off-targets, then it’s not likely that they will be a problem going forwards. Overall, I’d say that base editing is going to have the same hurdles but with minor modifications.

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