[0:00] thank you everyone for being here so late last talk, I'm Fernando Aleman, co founder and Chief Scientific Officer of Navega Therapeutics, and I'm going to change topics a little bit. I'm going to talk about epigenetic gene therapies chronic pain and beyond.
[0:45] the mission of Navega, we are a preclinical stage gene therapy company that is spanned out of UCD San Diego, and we aim to transform the treatment of chronic pain and inflammatory disorders through precise, durable and safe gene therapies. We do this with design of new zinc fingers through an AI enabled zinc finger epigenetic gene therapies. We are very proud of the partners that we have formed and some of the agencies that have been funding the company so far.
And our lead candidate is NT-Z001, an epigenetic repressor of Nav1.7 is a sodium channel responsible for pain signal transmission, very similar to the one that vertex announced this year, earlier this year, is Nav1.8 is another sodium channel involving in pain.
Now what is our platform? How do we do this? So we first have a DNA binding domain. Is kind of the GPS of the system, and this is composed of a zinc finger array. Each of these zinc fingers will bind to three nucleotides in the genome to actually specify a specific location, and then you can fuse either a repression domain, if your gene of interest you want to down regulate that gene, or an activation domain, in case that you want more RNA and more protein downstream.
So it depends on the application the target you can go to down regulation or up regulation. And I would like to spend some time talking about the advantages of epigenetic targeting so the DNA level, why we think that this has some favorable properties when you target the DNA, there's you can multi target and repress and activate even at the same time with one drug, the same as antibodies. Can target two proteins. We can target two genes simultaneously.
And the good thing is that there are only two targets per cell. Whenever you target DNA, when you target RNA, there are many molecules of RNA and many molecules of protein. But with DNA, there's always two and there's no DNA turnover unless the cell divides. So it's a more stable entity.
However, when you are targeting RNA or proteins you have you don't know the turnover sometimes of the protein or the RNA, it could be different. This turnover is not constant. It can depend on several environmental cues, hormones, light or day cycles and many others. It depends on the target, and it's a challenge when it's a high expressing gene, especially for RNA targeting modalities, you might end up, in a moment, having a lot of RNA molecules, and then the efficacy can be reduced. And then is that you could do with RNA targeting modalities.
You can have an effect in an animal, but then you change species, and then that expression levels or that turnover is different for human, something that would not happen with when you target DNA.
So the issue with zinc fingers, and the reason why most people transfer or change to CRISPR, is that zinc fingers, you need to design a whole protein. It's way more complicated than just CRISPR, just a guide RNA, that's way simpler. But zinc fingers, more than 50% of our transcription factors use a zinc finger to modulate gene expression. So there's a lot of knowledge there. What we have done is just incorporate all that knowledge from natural occurring zinc fingers and also in vitro and also proprietary screenings to actually have a model that to design zinc fingers as easily as you can Design Guide RNA, so you don't have to have most gene or protein design knowledge, and the model will come up with the protein itself. Now our lead compound, is targeting SCN9A that codifies for the Nav 1.7 channel.
This is a highly validated gene. People with a loss of function mutation, they don't feel pain whatsoever, and people with a gain of function mutation, there are a couple of rare diseases that goes with episodic pain. So highly validated target, and we have a wealth of knowledge.
This was published in Science Translational Medicine in 2021 this is one of the models of chronic pain. This is chemotherapy induced chronic pain. Here is the baseline, the group of mice that received the chemotherapy. You test that they are in pain, then you administer the therapy, and with only one injection, you have durable reversal of the pain phenotype in mice.
Here, this is a different model, this is carrageenan, because the other one was more neuropathic pain. This is more inflammatory pain. Here we have groups. You inject the inflammatory component, carrageenan, in one pot, and then you have the contralateral without carrageenan or the inflammatory marker. And then do you see that whenever you are using the zinc finger, our lead candidate, you can reverse the pain phenotype. But whenever you're you are using in the pot that is not inflamed, there's no difference between one or the other group, meaning the mice are not [unclear].
Because here, what we are doing is just using a laser that creates heat but is the same time that they with the stand the heat so they are not burning themselves.
And with one injection, using the same model, we went up to 44 weeks. So this is a really long, lasting therapy. We have performed some pilot NHP safety studies using different promoters just to determine which one was working better. One of the things that some of these gene therapies, it's well known in the literature, is that some of them can have dorsal root ganglia toxicity, but in our studies, we did not see any of the dorsal root conglotoxicity, and we also didn't see any mortality or morbidity, cardiac or neurotoxicity. We did see some neutralizing antibodies, as is normal with these gene therapies, the biodistribution, what was comparable with both promoters, and again, in histology, we did not see any growth effects. So overall, very safe drug using both promoters.
So what is our lead indication? Our lead indication for humans will be trigeminal neuralgia, which is called, sometimes a suicide disease. It's horrible pain. It goes with attacks. It's still considered an orphan designation, but our route of administration will be direct injection in the trigeminal ganglia. For those, it's already established route of administration with CPT codes, because there are some of these therapies, Gamma Knife and rhizotomy with glycerol. These alternatives that are now available are not very effective. And our therapy, again, the mechanism of action it will be the zinc finger going to the promoter region of the gene and reducing the amount of RNA and protein.
This is another sticking point of why zinc fingers were not used more, and why CRISPR-Cas9 exploded, is that sometimes when you design a new zinc finger, you might have the on target activity, but you did not have enough specificity. So this is something that we have able to achieve with our model integrating all this data. And this is an RNA Seq experiment. Here would be the genes that are upregulated. Here are the genes that would be downregulated. And apart from the genes that we kind of inserted either in the control or the zinc finger itself, the only other gene that appears in a whole transcriptome is our target now 1.7 so we were very happy with those results.
And lastly, this is a data using our lead candidate from trigeminal ganglia that we culture in the lab using three different human donors, and we see an increase in efficacy or percentage repression of the gene of interest, depending on those so we were very happy about that as well. So just an overview of the program we have more data in different pain models.
We have higher specificity, we have high durability as well, no safety issues in rodents or in nhp, and also some data that I did not present in IPSC derived nociceptors as well with some of the collaborators. And in short, we are looking to partner this program to some pharma companies that can help us move to clinical trials, more expensive clinical trials. We have these leads that I bring to you today. We have another lead candidate for rheumatoid arthritis that I didn't bring that not only reduces pain, but it also has disease modifying properties.
We have seen reduction in nerve sprouting. We have seen reduction in inflammatory markers in the joints. We are very excited about this one. This is a little bit farther from the clinic, but our data is really good, and we also have a discovery stage platform that we can apply for other gene of interest as well. And with that, thank you very much, and I'll take any questions.