Groundbreaking research is exploring the potential for harnessing a mosquito-borne virus to treat disorders such as neuroimmunity, neurodegeneration and schizophrenia.
Dr Benjamin Bartelle, of Arizona State University, proposes using the bioactivity of Zika virus, ZKV, by employing a breakthrough method called continuous viral evolution to adapt the pathogen to improve human health.
He says: “We can harness the unique biology of ZKV, similarly to how we have already engineered HIV and AAVs into tools for discovery and human health. Moreover, recent advances in bioengineering allow us to reshape the whole ZKV genome using continuous viral evolution, domesticating this wild virus into a powerful new class of therapy, capable of acting on multiple pathways to address the root causes of neurodegeneration.’’
ZKV operates by infecting neuroimmune cells, suppressing their inflammatory responses and stimulating autophagy – where the body consumes its own tissue. These are the processes needed in the treatment of neuroinflammatory and degenerative disorders but which previous medical strategies have been unable to deliver.
Microglia, the brain’s immune cells, are involved in almost every neurodegenerative disorder but have proved too complex for drug based therapies and highly resistant to established gene therapy vectors. ZKV, however, infects microglia and reprograms them to suppress inflammation and stimulate autophagy, the very processes that become disrupted in neurodegeneration.
Dr Bartelle says: “I had already been pushing into working on ensembles of proteins together and I’ve been at the edges of this sort of revolutionary method called directed evolution. And we’re just working out the directed evolution, the parameters and what works and what doesn’t.’’
The first step in the two-year project was to engineer the Zika virus itself and make a fully synthetic, or recombinant, version of the virus. This has been done and it works in tissue culture. Phase Two is starting an evolutionary paradigm and fine tuning it so that it only infects microglia. Then, starting next summer, the project will move to animal trials.
“We’re pretty much on target for, for getting this done,’’ says Dr Bartelle. “Of course, COVID delayed things, but it was one of those where there’s a lot of design work upfront.
“So even though it was difficult getting students, one thing about Arizona is it’s kind of cowboy culture, so we’re totally fine with being open despite getting sick left and right, for better or worse. So, when I first hired a student to do this right away, he came in and he hadn’t been vaccinated yet. So, he stayed away from the lab for a couple of weeks and we went through the design process together, just over Zoom and just had to do things on the computer. It’s not like there’s a real CAD for DNA, but there’s a lot of designs and stuff, but you plan out the work you’re going to do so we’re able to get that. So we started out a little bit delayed. I wanted to be a one to be rolling on this between December and March.
However, if the research is successful, he can foresee regulatory problems ahead.
“I think one thing that’s different is I’m trying to take this whole ensemble of genes and Zika and engineer them a certain way. That’s not innovative, because like no one thought they could do it. What it is, is, honestly, it’s risky, because with the approval process for drugs you have to focus on particular mechanisms. And the real risk here is, if we develop this virus, and it works really well, if it has multiple mechanisms working together, that’s going to be difficult to push through the SBA. It’s not that nobody thought this was possible, it’s that it’s going to be a credit nightmare turned into a therapy, no one wants to do.’’
He adds: “I do want to have an impact on public health but I also don’t want to do research that is best done in industry, that is best done by a pharma company, if it’s going to lead directly to a therapeutic and market. There’s a lot of pressure right now, why don’t we just do research that immediately goes to a phase one clinical trial? I don’t want to be that person, because that’s their job. So this is important for us to explore these new directions.’’
He adds: “The FDA is never going to approve it. Right? That’s a really easy missing thing to work out. That’s just not how it works. RNA vaccines – they have been trying to get this going since the 1990s. It’s not that they didn’t work, it’s just they had to move through the regulatory space very slowly. But yes, if they hadn’t been trying to get it to work for that amount of time, they wouldn’t have it now. So the point of basic science and academia is to get that ball rolling. If this does become something in 10 years, or 15 years. It’s only because we started it now.’’
Dr Bartelle has been supported in his research by the 1907 Foundation, a charity that funds medical research into mental health and supports young scientists whose work in this area has the potential to change the future.
“This is much too risky to be given funding by the FDA but I don’t consider it to be high risk. We have to remember that work in MRNA vaccines has been going since the 1990s and has moved very slowly through the regulatory space. It can take ten to 15 years for something to become a reality, and our project at this stage,” says Dr Bartelle.
“I am very pleased and grateful 1907 have given their support to this.”
Brady Smith, director of partnerships at 1907 Foundation, said: ”We can’t expect outsized reward without outsized risk. Dr. Bartelle’s research aims high and investigates a new class of therapy. We’re excited for what he finds.”
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