Genetic Epilepsy Team Australia’s 2025 Genetic Epilepsy Conference

Thank you so much for having me. And I would also very much to thank Danny and Danielle for the invitation to be here. It’s really a both privilege but also humbling to be with all of you and hopefully be helping as part of the overall ecosystem to bring new treatments to you all.

I’m an internal medicine physician scientist. I have in addition to taking care of patients very early on, got involved in developing therapeutics. I’ve actually worked across small molecules, gene therapies, and today I am gonna be talking to you about oligonucleotides. I. And as part of that background, I’ve actually had the privilege of bringing three of those products through the Food and Drug Administration.

You may be wondering Camp four, what’s the background around the name? So Camp four, for some of you Mountaineers may know that it is the final prior to the summit camp before getting to the top of a mountain, particularly of Everest. And we use this as a motivator for our team in terms of bringing new treatments and all the hard work that, that you’ve all heard about that goes in to developing new treatments.

This next slide is required by my legal department to share with you all. And my, my disclosures is that I’m an employee of Camp four. So Camp four is actually an 8-year-old company. We were spun out of the lab of Rick Young at the Whitehead Institute, that’s part of the Massachusetts Institute of Technology in Boston.

And Rick in particular is an expert alongside a collaborator of his named ZA at Boston Children’s around really trying to understand what controls transcription, what controls making ultimately the RNA from DNA. And and so the company was set up and has actually been at this for now eight years.

And so what I’m gonna talk to you about is an antisense oligonucleotide that we are actually developing for Synap one. We actually have a developmental candidate that we’ve declared, and I’m gonna show you some data, but we’ll give you a little bit more background. Antisense oligonucleotides have been used before, and I’ll show you some of them that have actually been improved and they can be used in different ways to actually control expression.

Many of these have actually been focused on degrading or reducing protein expression more in like gain of function type diseases. We, however, have developed an ability to actually map what are the control elements of different genes, and then actually use that to also upregulate. And I’ll talk a little bit more about that.

And so we’re developing this a SO for SYNAP to actually increase the amount of synap protein, which is absent. Before I mention some of the ASOS that are approved one thing that’ll come next to is you can see, and this has been mentioned quite well in some of the prior talks around, you have DNA and then pre mRNA and then mRNA, and then protein.

Some assos, particularly in monogenetic, epilepsies are focused on taking pre mRNA and actually increasing through splice modulation. The amount of then the final mRNA before it goes to protein. Where we are focused is actually at the development of taking the transcription of the DNA to the pre mRNA.

So it’s a slightly different area of functioning. But I think what’s also really important is that we now have a lot of experience around antisense oligonucleotides across different diseases and also across different delivery mechanisms. We actually at camp for running another trial that I’ll mention briefly in Australia that’s focused on a metabolic disease in the liver.

And so we actually administer that subcutaneously. And so the benefit of having these other assos that have been improved is we can understand the chemistry and the safety profile and use that same chemistry. And that’s really important to us is we’re not actually creating new chemistries. We want to use existing chemistries that we know are safe and that we understand how they can be used safely in trials.

I won’t spend much time here ’cause this was shared previously, but the intrathecal route is one of the main routes that we can use to get this into the brain. This has become quite common. It is obviously not without risks, like any procedure has risks, but it is something that neurologists do all the time.

And one of the benefits is it helps us make sure that we get the appropriate amount of the a SO to the relevant areas of the brain. And that’s really important as we think about different diseases because different regions of the brain may play more important roles, in particular conditions, and so we want to be able to do that.

The problem sometimes with administering it more peripherally, like either subcutaneously or in the IV is then the a SO goes to all the tissues of the body, and now you have to be concerned with what are some of those off target effects. So synap is a haplo insufficient disease. In this situation you have one good and then potentially one bad or mutated copy.

And the bad copy may either not be expressed or may be expressed but then degraded very quickly. And so you end up with typically around 50% or so less protein. And this is important for the disease. What we at camp four and I mentioned our founder, Rick Young identified, is that there are many components that are important for regulating the level of expression.

And in particular there are these kind of what previously were called non-coding RNAs. We have coined the term regulatory RNAs that control this. Some of them will activate or increase the amount of RNA that’s produced. Some of them will decrease them, repressors. And what we found is that if we, these repressors in particular have a binding site that ASOS combine to, so we create an a SO that’s specific to that reg, RNA.

We bind to it, it actually changes the confirmation of the repressor and causes it to come off the gene. And that is akin to taking your foot off the brake and the car would in move forward, or in this case the gene would increase expression. And so this can actually allow us to get to near normal syn gap levels.

And we actually have data on this just maybe to illustrate this a little bit more because there are different approaches. And I think we’re gonna see, and this is a very positive development, more assos being developed, but they may be being developed to target different parts of the pathway is you could think about a analogy of two dams, both at the top of a river, we’re trying to fill the reservoir and one of the dams is closed.

So this is akin to one of the alleles not being being mutated and not producing. So how do we fix this? So our approach is that we are going to have reg R-N-A-A-S-O workers who can actually increase the size of the dam openings and allow more water to flow through. We’re not able to increase the other one because it’s mutated and there’s it’s closed.

Another approach might be to, while you couldn’t, for example, increase the size of the openings, you could remove some of the rocks along the way or change or alter the path. This might be a claim akin to more splice modulation approaches. All right, so now I’m gonna show you some data. So just maybe to cover a, with a little bit more depth the approach.

So this is the chromatin loop at during transcription and as part of this chromatin loop, you can see the loop comes together and you have an active enhancer and promoter. And at that site is a complex that’s responsible for transcription. And actually this is very finely regulated. And so that’s where the regulatory RNAs can function.

And so when you look over the top of me, you can see, for example, in this case, this is the example of a repressor that might be on a particular active enhancer. And so we combine to that, remove that and increase gene expression. So how do we make these assos? We actually have developed a platform where we take many different cell types.

Oftentimes these are IPSC cells, and then we actually map all the regulatory RNA elements that are part of that cell type that are associated with particular genes of interest. And in fact, many of these genes have multiple reg RNAs. So we focus on identifying which are those that actually have a one-to-one relationship with the gene.

We don’t want to target a reg RNA that might touch many genes. We wanna focus on that one single gene that reduces the likelihood that we can have off target effects. We then actually use a variety of machine learning tools initially in silico before we go. In vitro and we actually make multiple assos.

We screen them electronically and then ultimately we make them and we actually screen them in cell lines. And so we’ve been doing this for a while. As I mentioned, we have a clinical trial that’s ongoing right now here in Australia for urea cycle disorders. This is a disorder that occurs both in children and adults where they are have a poor ability to metabolize ammonia into urea.

But our second program is synap and I’m gonna show you some data there. So on the left you’ll see here we identified that there were in fact multiple synap, one enhancers, and we also identified multiple types of reg RNA that were responsible. There. We identified a particular one that seemed to be most important for actually controlling overall expression.

And so then we developed ASOS to target that. And what you can see in the middle inset here is that the A SO when it bound to the reg RNA increased transcription and the way we measured this is by actually looking at increase in RNA polymerase two, which is a key machinery element for doing that.

When we compared that though to housekeeping control genes we didn’t see that same element. And then to the far right, what you’ll actually see here is now we’re actually wanting to look at mRNA that’s produced. And so we have a family for familial control. We then have a syn gap. Patient, IPSC.

We for the control used a non-target control. So it’s basically like a scrambled a SO that doesn’t actually target. And then you can see here two different assos that we created. And you can see both of them actually bring the level back to wild type, and that’s an mRNA, but what we really care about is protein.

So what about that? Over to the left, what you can see is that using this a this was in a mouse model where we were replace the syn gap mouse gene with a humanized mouse gene. And then we gave this a SO and we looked across different brain regions that are important here. And we actually saw a dose response, which gives us increased confidence then that a SO is actually producing the protein.

And then to the inset to the right. This shows that there was also dose responsiveness in a synap mRNA with a mouse surrogate, a so this is a little bit different. Rather than using the he humanized gene, what we actually did is created a special a SO that targeted this unique sequence for the mouse.

The mouse sequence and the human sequence are a little bit different. So we actually create these mouse specific, aSOS as well. And so we are working very hard to actually bring this a SO to patients in a clinical trial as soon as possible. And it’s gonna be really important that we all work together as an ecosystem to be able to help get the trial up and running.

One of the both opportunities but also challenges in Synap is because there haven’t been other studies of disease modifying or genetic therapies. We need to work together to figure out what are the appropriate endpoints, how do we measure them over what period of time? And so I just am really grateful for all the work that you’re doing here for this conference to be able to allow us to do that.

And then lastly, I’ll just say we are very excited. We’re gonna actually be presenting some primate data for Synap, and that’s gonna be at an upcoming conference in two weeks. It’s the American Society of Gene and Cell Therapy. And after this we’ll be working to also disseminate that data as we start to move towards being able to go into clinical trials.

So with that, I’m really grateful for the opportunity to be here. I’m grateful for the invitation and I’m looking forward to getting to know you all better and working together with you.