4.4.23-Health-Tiba-Biotech

JASDAVE CHAHAL: Yeah, my name is Jasdave Chahal and I'm going to talk about RNA delivery at Tiba Biotech. So my background was originally virology. And I snuck into MIT to become a post-doc, first at the Whitehead Institute where I was working really on vaccine applications, until they got sick of me, kicked me over to the Koch Institute, where then I focused more on the platform we had developed to deliver these large RNA payloads.

So I don't think we have to explain to people too much anymore that mRNA technology is very powerful. If you've received two of the most popular vaccines in the last few years, you might have felt the impact of RNA technology yourself. But when we were developing at my time as a post-doc, we were inspired by the biology-based way of encapsulating and delivering nucleic acids.

So I think of RNA delivery really as a spectrum of technologies. The entire world has more or less converged on lipid nanoparticles as the standard. So the basic secret ingredient is an ionizable or cationic lipid that can complex with a negatively-charged nucleic acid backbone, collapses into a nanoparticle, and basically that's your drug right there.

But we were developing off of inspiration derived from polymers, so large macromolecular complexes that can carry many positive charges that you can build in a lot of chemical flexibility into those systems. And they're very popular as transfection reagents going back decades. But we wanted to capture what polymers can do in terms of potency and things like that, but have it be as manufacturable as a small molecule product, because these are very large.

There's polydispersity associated with them. But we can capture that polymer-like activity by using these highly-branched molecules called dendrimers. And that's really the intellectual property space that Tiba now occupies after licensing the original patent for this kind of technology out of MIT.

Now basically these large-sized molecules that we're using to deliver nucleic acids, one of the fundamental things we wanted in the design was biodegradability I mentioned that if you felt the impact of RNA technology, you might have felt the impact of the side effects as well. It's well-known now in the field that lipid nanoparticles of conventional design are fairly inflammatory, which is great for vaccine application.

But we wanted to go in designing a system where that wasn't necessarily going to be the case, if we're looking forward to things like therapeutics in the future. And so we've proved that with our design, where we create the core of these highly-branched molecules out of a polyester-based scaffold. So this is highly biodegradable.

In an in vitro system, all of the molecules comprising our system are biodegradable, with half lives on the order of a few hours, the idea being that after administration to the patient, the delivery material should be negligible, should be almost gone after a day or so. And really the RNA is the pharmaceutical ingredient. So it's there to do its job.

And in some of our early studies, we wanted to show that the system works compared to a standardized lipid nanoparticle. We spent some time optimizing a standard LNP formula for gene expression in a mouse, showed that indeed we could beat the level of gene expression compared to that benchmark. But most importantly, we saw that we got negligible inflammation compared to the LNP. As expected, LNP dosing leads to a lot of pro-inflammatory markers in the blood of that mouse, and we were able to show that we can get greater gene expression without that side effect.

Now we've put a lot of effort into vaccines. That's where my background is. And that's kind of the low-hanging fruit for RNA technology. But in terms of partnering and looking forward, we're really thinking about therapeutics, where the biggest promise for RNA technology really lies. And I'm just showing a few sample bits of data to show that we have some opportunities in the space.

In particular, we're thinking about lung and heart. We've shown and published with some partners that we can administer our RNA-based particles into the nose of animals, get gene expression from the lungs. That led to nice potent T-Cell responses against a flu antigen, just as the demonstration case. But I think more interestingly we can get to really difficult to address organs like the heart.

And we've shown that by modulating our formulation parameters and injecting particles into the bloodstream of an animal, we can get increasing gene expression in the myocardium, which opens up a lot of opportunities in cardiovascular disease. So as I mentioned, we're working a lot on vaccines. That part of the business is self-sustaining now. There's a lot of partners and philanthropic groups, most recently a deal with CEPI to work on Japanese encephalitis virus.

But we are looking forward to lung and heart and hopefully soon oncology and neurology applications as well for the technology. And so we're specifically interested in potential partners with expertise in these areas, in particular cardiovascular disease, groups with knowledge of the relevant models and indications that are interested in partnering with a company that can essentially get you there with your nucleic acid of interest.

So if you want to talk to us, we've got a booth right next door and happy to talk more about RNA delivery.