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Repurposing Zika

Oncology drives you to some pretty strange ideas about therapy. But that’s understandable – in what other field are you trying aggressively to kill off parts of the patient’s own body? That’s why chemotherapy started off with the study of people who had been exposed to mustard gas (during the Bari bombing raid), where it was noticed that systemic exposure to such brutally reactive compounds killed off fast-dividing cells before (just before) they killed off the rest.

We’ve come quite a ways since chemical warfare agents, although nitrogen mustards, never forget, are still in the pharmacopeia. There’s a new idea, though, will remind people of just that sort of desperation move. I was writing not long ago about glioblastoma and what an awful form of cancer it is, so it might not surprise you that it invites some of the wilder ideas for treatment. So, you’re looking for something that can reach in and kill off brain cells – not all of them, of course, just some of them – so what might you have seen recently that seems to go in and attack certain brain cell populations? Got it – how about Zika virus?

That’s the subject of this new paper from a multicenter team (Washington U, UCSD, Cleveland Clinic, University of Texas Medical Branch).  (Here’s a press release). The terrible effects of Zika infection on a developing fetus are due to its effects on neuronal precursor cells, and it appears that the virus can attack the stem-cell-like population that’s such a problem with glioblastoma. One reason that this isn’t quite as crazy as it might sound is that glioblastoma tends to stay put – it’s very rarely metastatic, and after surgery (when that’s possible) it tends to recur in situ, from residual cells that can’t all be removed. So you don’t need to infect a patient’s whole body – just a localized shot of (attenuated) virus might do the trick.

And oncolytic viruses are, of course, not crazy either. There’s been a lot of work put into this general idea over the years, with recent hints of more success. There’s a virus approved for melanoma, although the jury’s still out on how effective it is, and several more in development. So Zika’s cellular targeting might be just the thing, and its effects in adults are notably less severe. (You do wonder, though, what the population of neuronal stem cells is like in the adult brain, whether wild-type Zika infections clear some of them out, and what the long-term effects of that might be). The mechanism by which Zika preferentially goes after these cells is unknown, but appears (as you might well imagine) to be based in different immune presentation by different cell populations.

The paper tries several patient-derived cell glioblastoma cell cultures and several strains of Zika virus, and it does seem to infect them readily, as opposed to differentiated glial cells, which are almost untouched. Experiments on tissue removed during glioblastoma surgical procedures (and control brain tissue removed during epilepsy surgery) confirmed these results. Related flaviviruses (like West Nile) don’t show this kind of selectivity. The authors went as far as mouse glioma models (and a mouse-adapted form of Zika) and demonstrated growth inhibition of the tumors, although this is arguably getting a bit far afield as compared to the results in human tissue.

The authors went on to use an attenuated form of the virus (with a mutation in its NS5 protein that inhibits replication) and showed that it still seemed effective (although wild-type was better) – and what’s more, the combination of it with the standard of care for glioblastoma, temozolimide, was additive. Their proposal is to keep working on the replication-crippled mutant virus to develop something that is worth taking into the clinic, and it should be noted that other viruses are being worked on for glioblastoma by other groups for the same end. Those are also eyebrow-raisers in some cases (polio!), but that’s how I started this post: oncology leads you to some pretty wild ideas. Good luck to all involved – glioblastoma is awful, and we need all the help we can get against it.

19 comments on “Repurposing Zika”

  1. anon says:

    Not a biologist here. I thought viruses can mutate and evolve. Wouldn’t a treatment with a virus make it more dangerous? Soon we will have a more lethal Zika. Am I wrong?

    1. Derek Lowe says:

      Beating down their replication pathways, in ways that are unlikely to revert easily, is the plan to deal with this objection as I understand it.

    2. David says:

      Is not the primary concern that it will evolve resistance to the treatments/drugs we use to fight it? If those drugs (or similar) are not being used as part of this treatment, it’s unlikely they’ll come in contact with anything we’re concerned about an evolved resistance developing to?

    3. Patrick says:

      Zika primarily spreads via mosquito bites, so it’s not at high risk for spreading in a clinical setting.

    4. Luke Weston says:

      Zika is not a particularly dangerous virus. It’s pretty much just a ‘flu, clinically.

      Like Rubella, the chief danger from Zika is that it’s teratogenic.

  2. David says:

    Yet another example of the adage “the dose makes the poison” – even an infection can be positive in the right degree and context?

    1. a. nonymaus says:

      This approach always works well with no side effects in zombie movies! 😉

    2. aairfccha says:

      Yes. For a much older example, look up Malariotherapy.

  3. Jon says:

    ” So, you’re looking for something that can reach in and kill off brain cells – not all of them, of course, just some of them –”

    Okay, this will get me kicked off, but I had to answer, “Fox News”.

    J.

    1. Isidore says:

      You are right, CNN and MSNBC will kill all of them. 😉

      1. Pennpenn says:

        Yeah you’re already functionally brain dead if you’re watching Fox News…

  4. Lane Simonian says:

    This is walking a real fine line. Viral infections can generate reactive nitrogen species that can kill cancer cells (but as often-noted healthy cells as well) and they can potentially in some circumstances activate an immune response against cancer cells.

    https://www.ncbi.nlm.nih.gov/labs/articles/16955520/

    https://www.ncbi.nlm.nih.gov/pubmed/20089706

    On the other hand, reactive nitrogen species can also damage immune responses.

    http://www.jimmunol.org/content/162/6/3356

    This is going out on a limb as well but one may be better off instead of trying to create reactive nitrogen species to treat cancer to try to remove them instead.

  5. Mark Thorson says:

    You know, another brain-eating virus is rabies. Maybe an attenuated rabies virus would have some application. I anticipate their might be some perception problems with it.

    You want to do what?!?

    1. truthortruth says:

      I think the public is starting to come around on this, especially with gene therapy, where we use HIV (lentivirus) to deliver nucleic acids.

      1. Wiseguy says:

        There’s a reason we call it lentivirus and not modified-HIV! You won’t find many patients signing up for the latter.

    2. Barry says:

      rabies virus has recently be repurposed–not as a therapeutic–but as a mapping tool exactly because it is transmitted synapse-to-synapse rather than through the circulation.

      1. AC says:

        It is actually a herpesvirus, called pseudorabies, that is used to map synapses.

        https://en.wikipedia.org/wiki/Pseudorabies#Applications_in_neuroscience

    3. AC says:

      Great guess! Rabies was actually the first oncolytic virus used in a clinical study (sometime in the 1950s). It is still being developed as a treatment by some researchers at the Mayo Clinic.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516024/

      1. tangent says:

        … Holy hell.

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