CRISPR-Mediated In Vivo Epigenomic Activation
Daniel Hart, PhD, the senior director and head of technology development at Epic Bio, discussed potential applications of the new technology.
Daniel Hart, PhD
Epigenetic regulation approaches hold the potential to modify expression of a particular gene without modifying the DNA of the gene itself. Such approaches have traditionally focused on gene silencing. Epic Bio, however, is seeking to use a CRISPR-mediate approach to epigenetic regulation to activate expression of specific genes.
Daniel Hart, PhD, the senior director and head of technology development at Epic Bio, presented research on this topic at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024. CGTLive® interviewed Hart at the conference to learn more.
CGTLive: Can you tell us about your work with epigenetic activators?
Daniel Hart, PhD: The research behind our epigenetic activators and the rationale for developing them is that over the last 2 to 2.5 years, we've become interested in this other side of epigenetic regulation, which is that you can turn genes on. I think people are familiar with the idea you can turn genes off with epigenetic editing, but switching them on is something that has not really been demonstrated before. We set up screens to identify these factors and [were] successful in doing so. Now that we have them, I think the challenge is understanding what the best applications would be for them, but I think it's easy to imagine deploying them in diseases known as haploinsufficiencies. These would be conditions where you have half or less than half the amount of the desired protein. You could imagine putting these activators in place to turn on the good copy to restore full levels of protein expression. That's something we're very excited about and that's something we're actively pursuing.
Can you give an overview of the key points from your presentation?
I think the main takeaways are that we have found a class of activator that has at least 1 of 3 important attributes. The first is that it would be robust, meaning that it can activate genes in different contexts. To add a little more color to that, genes can be quiet, nonexpressed, moderately expressed, or very, very highly expressed. Having an activator that can turn on genes in all these 3 categories will be really nice. Secondly, is that the activators are potent, and that means that they could really turn the genes on to a very high level. And then lastly, that in doing so, they could turn genes on durably through mitotic cell division—so you deliver this activator transiently to cells, and yet it achieves lasting changes in expression. That's what we've been trying to achieve.
Coming off these findings, what research do you think needs to be pursued next?
Further research on these findings, I think, will center on a number of things. What we showed at ASGCT this year is really the discovery of these things and initial characterization of them. But as with any biotechnology that you are hoping to deploy in a therapeutic context, there are a number of aspects—for instance, safety and efficacy and things like that—can we improve the activations that we've shown, can we get them to be even more long lasting? Can we get them to achieve persistent activation across different cell types and different targets? Can we show this in vivo, in a more therapeutically relevant context? Then on the question of safety, how specific is the effect? Are there any toxicity issues related to deploying such an activity? All these things remain to be demonstrated, and we're actively pursuing all of them. It's a very exciting space, and it's nice to be at the forefront of this type of work.
Is there anything else upcoming from Epic Bio that you can share?
Exciting news around Epic I think is that we have tried to fulfill our mission to be the lead epigenetic editing company in the space, and in doing so, we're very excited about bringing this technology to the clinic, which we're on pace to do. We think we're going to be the first ones to do that. It's always exciting to pioneer something. I think that's the most exciting aspect of the work that we do at Epic.
Is there anything else that has excited you at this year's conference?
Without being too biased, I think the more prominence given to non–gene-editing approaches has been exciting to see; RNA editing, for instance, episomal delivery for lasting changes in gene expression, the kind of work that we do in the epigenetic editing space—this is really, really exciting.
There have been, of course, breakthroughs as well in cell and gene therapy that everyone else will be hearing about. But the thing that I take away from this conference that I'm most impressed with is the clear focus on trying to bring meaningful therapies to people who need them. That remains in spite of the fact that this conference is growing and there are more and more people at play here. It's a fantastic conference I've really enjoyed.
This transcript has been edited for clarity.
Click here to view more coverage of the 2024 ASGCT Annual Meeting.
