Anelloviruses, a Potential Alternative to AAV for Gene Therapy
Chris Wright, MD, PhD, the chief medical officer and head of translational research at Ring Therapeutics, discussed research presented at ASGCT 2024.
Chris Wright, MD, PhD
Adeno-associated virus (AAV) vector-based gene therapy has provided a transformational new treatment modality for some genetic diseases, but the approach has some shortcomings. One of these is immunogenicity, which prevents redosing if the initial dose is insufficient or the effect of the therapy wears off over time.
Ring Therapeutics is seeking to use anellovectors as potential alternatives to AAV vectors for gene therapy in order to address this issue. At the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, the company gave several presentations on its research. At the conference, CGTLive® interviewed Chris Wright, MD, PhD, the chief medical officer and head of translational research at Ring Therapeutics, to learn more.
CGTLive: Can you tell us about Ring's platform and its potential advantages?
Chris Wright, MD, PhD: There's a lot of great potential for gene therapy. You're here at the gene therapy conference, there's a lot of people, and everybody is excited about making a difference for patients that really need therapies. One of the challenges with current gene therapy, while it seems to be working in some areas, is that there's problems with it being immunogenic. You get safety problems because people recognize it as foreign, and then they have a reaction. That can lead to problems from the safety perspective, with side effects and the like. It also makes it challenging to give it to everybody because many people already have antibodies to the viruses that are used for gene therapy for the most part these days. So ideally, you'd like to find a virus that wouldn't have those properties, that you could give maybe even repeat doses of if you need to, and that wouldn't cause any side effects and could be given to a broader population of people. That's one of the main areas that Ring is working on.
In order to try to understand, the viruses that might be suitable—that maybe have better properties—the company thought that maybe the best virus around is actually inside of us. What I mean by that is that it's known that the body has a bunch of viruses that just kind of hang out there and aren't doing anything harmful. People have heard about the microbiome, which is all the kind of bacteria in your body, but there's also a human virome, which are all the different viruses that are in your body. We were looking in the body for different viruses that are persisting there, but not causing any problems. We did find a number of viruses, and those are the anelloviruses. Anelloviruses actually make up about 80% of all the viruses in a person's body. And it turns out that that they've been there throughout all of the person's life, pretty much shortly after birth. So, they persist for a long period of time, and they don't appear to cause any problems, they don't induce an immune reaction, and they don't seem to have any associations with diseases. So, we thought that could be a great virus to use to try to deliver gene therapy because it should be a safe approach.
Can you give an overview of Ring's presentations at the conference?
We're fortunate to have 3 different abstracts accepted. We have 2 abstracts that were posters, and then I was able to have a talk that I'll be giving tomorrow. The posters are around some of the science. One thing about viral capsids is that sometimes they can only contain a certain amount of therapy. The idea is the more therapy you can get inside of it, the bigger the gene [can be], the more likely you're going to be able to treat many different diseases. We had one poster that showed that we could increase the size of the therapeutic gene. That was kind of a great advancement... The other poster is looking at how we're able to transduce different tissues, particularly in nonhuman primates (NHPs), in the eye. Getting to an NHP study is one of those studies that's very close to getting into humans eventually. So if you can take your new gene therapy and show that you can safely dose NHPs, that gives you a higher level of confidence that you can get into a human study sooner rather than later. That poster showed when we injected in the eye, we could get expression there. It was also the first time we demonstrated that you could put a gene in that is a therapeutic gene, and that you can have expression of that, as well. We showed that DNA and RNA was expressed in the NHP eyes, and that's sort of along the lines of the therapies that we want to develop. That was exciting to see. Redosability is also very important because right now, gene therapy is one-and-done. If you give it once, you can't ever give it again. And so what happens is sometimes maybe you underdose, and the person doesn't get the adequate response that you'd like them to have, but you can't do anything about that, or you might want to increase the duration of an effect—so sometimes gene therapies wear off, and then if you can't redose, then you're also kind of stuck.
This gives us the possibility to redose or to dose multiple times up front to get to the right therapeutic levels... It turns out that the outside of the capsid has pieces that are very variable, and so that means they're not really easily recognized by the immune system, and the parts of the capsid that are less variable are kind of hidden on the inside, so they can't be accessed by antibodies. So it's probably one of the reasons why it's immune silent. If you look at AAV, it actually has all of the more constant and nonvariable regions of the protein on the outside of the capsid. That kind of explains a little bit why it might be immune reactive, and why anello vectors might not be... This is all foundational knowledge that Ring discovered along with collaborators; in this case, it was at Johns Hopkins that collaborated to understand if there's any antibodies already in the body that recognize proteins on the capsid of the anello vector. If you look at all these capsid proteins and you try to find antibodies in human serum, you actually really almost find none. But if you look at other human viruses like HIV or HSV or even AAV, you see a lot of reactivity. That sort of also proved the point that anello viruses are sort of immune silent because they don't produce antibodies in people...
As I mentioned before, redosing is important because gene therapies can wear off, or you might not get the dose right the first time and you can't give it again. We did some experiments where we showed we could inject an anello vector that produced a marker that we could measure in the animals, and we showed that when you redose it, you actually get increased levels of the DNA, and when you redose AAV you actually got decreased levels. So that kind of speaks to the fact that with AAV, you're probably inducing an immune reaction, which means when you try to dose it a second time, you're not getting quite as much of the virus in the system, whereas with the anello vectors we saw actually a little bit of an increase in the liver in particular, and that's one of the organs where gene therapies tend to wear off.
We also did another study looking at redosing in the eye in NHPs and in that experiment, we actually used a aflibbercept, which is our disease gene. The first one [we did] was kind of a marker gene, just like a proof-of-concept to show that we could do redosing. Then the second study was in NHPs, where we were injecting in the eye with a therapeutic payload to see whether we could redose there. We were able to show that we can actually redose there, which was really nice. If you give 2 doses, you get a lot higher DNA and RNA. In particular with eye diseases, some of the current gene therapies that are AAV-based sort of are starting to run out of steam. Their efficacy goes down after about 6 to 12 months. That's not a great situation to be in if you can't redose. So in our case, we could give a gene therapy and if the efficacy wears off, we could treat again to prolong the efficacy, and help patients for longer.
This transcript has been edited for clarity.
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