As Gene Editing Technology Advances, Numerous Potential Modalities Emerge

Janice Chen, PhD
Credit: Mammoth Biosciences

Gene editing is an important area of interest in the rapidly evolving field of genomic medicine. A wide range of approaches to gene editing are currently in development across companies and academic institutions.

Notably, 4 different approaches to gene editing were discussed in a session entitled "Advances in genome editing: in vivo small edits and the promise of large insertions” the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD. Shortly after the session, CGTLive® sat down with Janice Chen, PhD, the cofounder and chief technology officer of Mammoth Biosciences, who served as a cochair of the session. Chen went over the various presentations in the session and their broader implications for the field of gene editing.

CGTLive: Can you give some background about the session you cochaired at ASGCT this year?

Janice Chen, PhD: The session this morning was called "Advances in genome editing: in vivo small edits and the promise of large insertions”. The goal of this session was to cover the diverse set of novel gene editing technologies that have been discovered over the recent years, moving beyond classical gene editing, which involves creating double-stranded breaks and oftentimes generating small edits, to now where the field is evolving, which is to bring in more flexibility to create larger gene insertions and to create greater versatility in the type of editing that can be done to treat genetic disease. The other part of this session also covered advances in clinical trials—so being able to take legacy CRISPR-editing technologies and moving those into patients. We learned about results from the recent HIV clinical trial in terms of trying to edit and permanently repress HIV in patients.

Can you give an overview of the key points that were discussed during the session?

We had 4 really great talks, which were also highly diverse. The first talk focused on programmable gene insertion. This is a new technology that enables large integration of sequences at certain loci and the goal is to be able to utilize a native locus to actually insert these genes to be able to treat certain diseases. This is a new technology that's been developed by Tom Biosciences. The speaker was sharing recent data, and also some of the advances in nonhuman primates. That's been very exciting to see the technology move so quickly beyond sort of in vitro proof of concept all the way through testing in larger mammals.

Later in the session we heard from Monda, who talked about the use of gene editing for neurological disorders, with a focus on spinal muscular atrophy (SMA) and being able to use base editing to basically modify SMN2 into SMN1 to generate a permanent treatment for SMA. Right now there are on market therapies that has been effective, but there are still limitations in terms of how durable those those doses are and also what is still needed in terms of generating that permanent cure for the disease.

After that, we heard from Erik J. Sontheimer, PhD, who spoke about a new technology called DNA polymerase base editing. This is sort of a theme on RT editing or prime editing, which the field has been really excited about in the recent years. But DNA-based editing addresses some of the challenges with RT editing, which is really to advance the fidelity of this type of gene writing and also circumvents some of the challenges in terms of being able to bring in such a large RNA payload into the system—so potentially also overcoming some manufacturing challenges.

And then, as I mentioned, the final talk was really recent data on the phase 1 clinical trial from Excision Therapeutics, using a novel technique of a multiplex Cas9 system to excise HIV from patients living with the disease. The investigator was able to share some data around the safety and tolerability of this particular treatment. Of the 5 patients that were enrolled in this trial, they did show very reasonable safety profiles. But also, I think, it still has to be shown whether or not this particular approach is going to be effective in eliminating HIV from these patients.

How would you summarize the big picture implications that doctors and the healthcare community should take away from the session?

I think it's very clear that gene editing is here to stay. We now have the first-generation technologies being addressed in clinical trials and patients being cured of diseases. I think the other exciting piece is how quickly the field is evolving to recognize that in order to actually address the broad range of genetic diseases we need all kinds of approaches to be able to fix the underlying root cause of disease. This session and ASGCT more broadly highlights that there's an ongoing pipeline of not just indications that are being treated, but also a pipeline of new technologies that are moving through and maturing rapidly.

Were any of the challenges in this space discussed in the session?

I think with new technologies, you're often running into some conflicting challenges. For instance, with base-editing, obviously, it's a very new and powerful technology, but still has limitations in the ability to have targeted delivery or fit into capsids to enable targeted delivery. I think that's an example of something that's holding back some of these larger modalities. The other piece is with DNA base editing or DNA polymerase-enabled editing—these require a DNA template, and so they can't be genetically encoded like a prime RNA can be, so that also introduces a conflict because you're able to increase the fidelity with these DNA polymerases, but then you've got to face the other challenge of how are you going to deliver these components to cells? So I think the field is going to have to work with these tradeoffs and depending on the particular disease and what patients need, we'll have to work through the different possibilities to find the best solution.

Is there anything else you would like to share with the audience?

I would just say ASGCT is just a really fantastic conference. It really brings the best of all of the contributors in the field, from industry, to academia, to nonprofits, and it's just really been a pleasure to be part of the community. I'm looking forward to seeing all the advancements translate into real therapies.

This transcript has been edited for clarity.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

REFERENCES
1. Chen J, Cong L, Kakkar R, Arbab M, Sontheimer E, Presti R. Advances in genome editing: in vivo small edits and the promise of large insertions. Session at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland.