Caribou Biosciences' chRDNA Technology May Enable New Treatments for ATTR and Familial Hypercholesterolemia

This is the second part of an interview with Steve Kanner, PhD. For the first part, click here. 

Steve Kanner, PhD

Caribou Biosciences conducting preclinical research evaluating its Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology, which is delivered by lipid nanoparticles (LNPs), for the treatment of transthyretin amyloidosis (ATTR) and familial hypercholesterolemia. The company recently presented mouse data from this research at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.

Shortly after the conference, CGTLive® interviewed Steve Kanner, PhD, the chief scientific officer of Caribou Biosciences, to learn more. Kanner emphasized the promise of the early findings and pointed out the work that still needs to be done before the technology can be brought to the clinic.

CGTLive: Can you give an overview of the key results that Caribou presented at ASGCT 2024?

Steve Kanner, PhD: We evaluated both efficacy and safety of these LNPs and we targeted 3 different genes in the liver. One is a transthyretin (Ttr). This is a well validated target. There's 2 products on the market, an LNP-based sRNA and a GalNAc-based sRNA. These products target transthyretin, which is a protein that through mutation can misfold and cause neuropathy and cardiomyopathy and so it's a very important target. We thought that based on its well-validation that a one-and-done approach, using a CRISPR methodology to knock the gene out, rather than to use sRNAs to inhibit it and then have to give the therapy over and over, would be very interesting. So we decided to start with that one.

Another 2 targets that we looked at address hypercholesterolemia. These are patients that don't have high cholesterol like many people have around the world—this is extraordinary levels. This isn't like "Oh, I'm over 200," this is like in the thousands. To address these types of patients, there's a couple of targets, 1 of which has been well validated by therapeutics, antibodies, and sRNAs, called proprotein convertase subtilisin/kexin type 9 (Pcsk9) and 1 that's emerging called angiopoietin-like 3 (Angptl3). That one's in clinical trials and probably will become a drug either in the antisense or sRNA world first. But we thought that that would be a really interesting approach because it's something we can measure in mice. We could look for the knockdown of the genes and we could test the level of suppression of the cholesterol. Then in the case of the Ttr, we could look for the reduction of the protein.

In all of these cases, we saw reduction of the level of expression of the proteins in the serum. We so we saw the reduction of Ttr, Pcsk9, and Angptl3 proteins. And then in the case of the 2 that address cholesterol hypercholesterolemia, we saw reduction in cholesterol. In the case of ATTR, we saw a 98% reduction of the Ttr, which is extraordinary, and would keep pace with what's been observed using sRNA approaches. As for the cholesterol, these are earlier and not as well optimized yet, but that's an interesting approach because there you could think about a dual approach. Maybe you give a therapeutic that addresses both genes at the same time and that would suppress the levels of cholesterol. But those were more modest. I think we saw about 25% to 30% reduction in cholesterol individually and we haven't yet evaluated them in combination, but we'll be looking at that soon.

How would you summarize the key takeaways of this for the healthcare community?

As I described, many of the approaches for these liver targets have either been generated through monoclonal antibodies, sRNAs, or antisense drugs—predominantly, not exclusively. Really thinking about how you get to a therapeutic that is better for the patients and if they could experience a single treatment that could get them to where they need to go with in terms of disease modification, that would be very attractive. So I think really the development of a therapeutic level CRISPR agent that could achieve this—and some of our competitors are looking at that now and have moved on into the clinic—that's a very attractive modality.

Are there any challenges that have been encountered so far that you can discuss?

I think we've demonstrated now in the presentation last week that there's 6 months durability of a single treatment in the Ttr. I think that showing further durability and showing this in nonhuman primates would be important. Understanding the safety profile is important. We did show in the talk that there's no off-targets detected. This is the basis of our chRDNA technology. We saw no off-targets. We didn't see changes in liver enzymes and we didn't see changes in body weight in the mice. But I think a better understanding of safety at high doses and in other species would be important. Other things are that this was all preclinical and this is research only and so we would need to develop a therapeutic level material and be able to scale that through manufacturing to be able to deliver this clinically and commercially.

Is there anything else you would like to add?

I think in general there are many different targets through which a technology like this could be applied and what we've demonstrated in this talk is really just scratching the surface. There are many different disease areas where we could address gene knockout, but I think the other thing that we're looking at is gene correction. There are many diseases where a gene is expressed in the liver, but it has a single point mutation. If you could correct that mutation, not only might you alleviate issues with the liver, but it may affect other issues that patients experience. So I think introducing genes is kind of a next wave of interest for us and seeing: Can we do a gene correction? Could we even do a gene insertion? That would be a higher order capability.

This transcript has been edited for clarity.

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

REFERENCE
1. Losa-Llabata M, Rajmane P, Stanaway L, et al. Cas12a CRISPR hybrid RNA-DNA (chRDNA)-mediated in vivo genome-editing technology for efficient and functional hepatic gene disruption. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland. Abstract #278