Monday, July 16, 2018

BacterioFiles 347 - Adenovirus Adapter Allows Assignment

Virus and shielded virus
Schmid et al, 2018, Nat Commun
This episode: Adding adapters to anti-cancer virus helps it avoid destruction by the body so it can target the tumors!

Thanks to Dr. Andreas Plückthun for his contribution!

Download Episode (7.8 MB, 8.5 minutes)

Show notes:
Microbe of the episode: Tomato leaf curl Vietnam virus

News item

Journal Paper:
Schmid M, Ernst P, Honegger A, Suomalainen M, Zimmermann M, Braun L, Stauffer S, Thom C, Dreier B, Eibauer M, Kipar A, Vogel V, Greber UF, Medalia O, Plückthun A. 2018. Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. Nat Commun 9:450.

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Episode outline:
  • Background: Viruses are very capable relative to size of genomes
    • Maximize tricks to streamline their lifestyle
  • Can coopt these tricks to our own advantage
    • Ex: targeting cancer cells specifically, or gene therapy
  • Gene modification makes this even more powerful technique
    • Increasingly as genetic tech/knowledge improve
  • What’s new: Now, Andreas Plückthun and colleages, publishing in Nature Communications have modified a respiratory virus to be able to target certain cancers specifically for gene therapy!
  • Methods: Virus is adenovirus – normally causes flu-like symptoms
    • Can hang out in infected cells and express genes there, without integrating into chromosome
  • Here's Dr. Plückthun explaining the challenges with using this virus: statement 1
  • Statement 2
    • Showed this adapter could help binding to desired cells
    • And prevent binding to others
  • Found that modified virus can get in to tumor cells and express genes inside
    • Luciferase here, to test
    • And much less light produced in liver, not much at all elsewhere
  • Statement 3
    • Sorta like shield to protect it, or camouflage so undetected
    • Does it work? When unshielded added to cells along with antibody, much less infection
      • Vs. no antibody
    • But when shield attached, infectivity much higher
    • Also showed shield doesn't interfere with targeting to cancer cells
    • Also helps prevent virus from going to organs too much instead of tumors
  • Statement 4
  • Summary: Common cancer-targeting virus modified by mutation and molecular adapters to avoid capture by the immune system and infect tumors specifically
  • Applications and implications: So seems like good system for treating tumors
    • Just need to put in the right stuff for effective gene therapy
    • Didn't show that here, just targeting/specificity
    • Add genes for producing antitumor treatments directly inside the tumor
  • Also useful cos reduces modifications needed
    • Only need to generate payload, then attach adapters
    • Instead of modifying payload + targeting stuff
  • Clarifications if necessary: Though viruses going to organs decreased, not much more to tumor
    • Might be limits on how many can enter
    • Where are the rest going?
    • Need to do more research to find and retarget better
  • What do I think: Impressive to be able to figure out/find molecules that accomplish things
    • Hard to build and hard to test cos so small
  • Very cool technology
Author Transcript:
If we want to use the virus for actually curing a serious disease, for example cancer, we have to achieve three things: first of all we have to get rid of the viral genes that cause these symptoms, and have to replace them by genes that encode something useful, for example make a therapeutic protein, or several therapeutic proteins. The second thing that we have to achieve is to teach the virus to infect those cells that we tell it to. The third thing that we have to achieve is to hide the virus from the immune system and from other cells that it shouldn't infect. And so in this paper, we have described how we solved these problems.

So to make the virus bind particular cells, you have to know what the structure of the virus looks like. It's an icosahedron, and at the vertices, comes out a fiber and at the end of this fiber is a fiber nob. So we've made an adapter that binds to these fibers extremely tightly, it doesn't come off over ten days, and at the end of this adapter is yet another protein which we can freely choose, which makes it bind to particular receptors, for example on cancer cells. And so thereby the virus gains affinity for the cancer cells.

So the third thing we had to do is hide the virus from the immune system and from other cells that it shouldn't infect. And for that we used a single-chain antibody which we again trimerized so that it binds extremely tightly, and thereby hides the virus from the immune system and from other cells.

So we've injected this heavily engineered virus into the tail vein of mice, and found that it really infects cells in the tumor. So we're very excited about that.