Genetic surgery, gene therapy but less scary

07.08.2014
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Scientists at Temple University School of Medicine have blocked HIV gene expression in human cells in a manner that reduces toxicity, suggesting it can "provide a specific, efficacious prophylactic and therapeutic approach against AIDS." But how was this finding shared with the public?

I recently saw a friend post an article titled Scientists Successfully Remove HIV From Human Cells. It’s not necessarily in her nature to post things of the like, so, intrigued, I had to take a gander. This article, while brief, successfully emphasized to the public that, “We have a cure for HIV elimination.” I was excited about the finding but disappointed that the best explanation of how this amazing cure worked was that they used “molecular tools that can operate on DNA.”

Rather than citing the journal and the specific paper that shares this finding, this article shared a link to another article with nearly the same title. Here, again, I found an interesting description of how this cure is supposed to work. This time they put it as “genetic surgery,” which elicits imagery of the operating table, the respectable surgeon, and the anesthetized patient lying there entirely vulnerable, a well-known and accepted part of medicine much unlike gene therapy, which is the real tool in use.

Again, this article had no reference to the specific paper, but luckily, Dr. Kamel Khalili, the senior author of the paper, was quoted heavily throughout both articles. Knowing the name and the topic, I easily found the paper in question in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) titled “RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection.”

In contrast to its description to the general public as “genetic surgery”, these tools are actually proteins that act in a similar way to the zinc finger nucleases mentioned in my previous HIV-related blog post. The tool used in this case is Cas9/guideRNA (gRNA) system that combines the scissors (Cas9 nuclease, a protein that creates a DNA double strand break) with a guide (RNA, which recognizes a 20 basepair sequence). Together, these can create breaks in DNA at specific locations, which upon repair, can create mutations in the genetic sequence.

Why do we want to break the DNA? Well, HIV – as a virus – inserts its own DNA into human DNA to replicate. Therefore, if we can prevent expression of its genes, we can prevent it from replicating. Current methods for treatment include antiretroviral drugs, which inhibit the active replication of the virus, but what about the cells where it inserts its DNA and lies low for a while to hide? It is this permanent integration of HIV-1 into the host genome that truly makes AIDS incurable. That’s where this tool comes in.

The researchers designed guides that targeted a region of the HIV genome that contains a highly conserved long terminal repeat (LTR) that has previously been shown as an effective target for removing the proviral DNA from the host cell. Most importantly, these guides were designed to minimize binding to the normal human DNA to prevent deletions in other essential parts of the genome and thus reduce toxicity. While this and similar techniques have been used to alter gene expression, they have been found to be highly insufficient and only partially selective and so, their potential for use in the clinic has remained minimal up to this point.

To eliminate toxicity, the researchers did a screen of the genome to find target sequences that avoided conserved sequences in human DNA. They then showed that targeting these sequences could suppress expression of viral genes even when there’s more than one copy of the viral genome present by creating mutations from the double strand cuts and measuring gene expression. According to the researchers, this suggests that it “can alter the DNA sequence of HIV-1 in latently infected patient’s cells harboring multiple proviral DNAs.”

Furthermore, they suggested that this tool could be used to immunize cells against HIV-1 infection. This is supported by the observation that cells expressing this tool were not conducive to HIV replication. Therefore, the tool “may provide a viable path toward a permanent or ‘sterile’ HIV-1 cure, and perhaps provide a means to eradicate and vaccinate against other pathogenic viruses.”

It’s a great finding but alas has quite a ways to go before it becomes applicable in the clinic. Remember that this proof of principle occurs in a dish where cells are relatively easy to manipulate. The next major challenge is figuring out how to effectively apply it to a whole organism and again, show that it works in that setting. Once determined to be effective and safe in lab animals, it can potentially be brought to humans to again determine whether it’s effective and safe. Perhaps some day it might become a real clinical application for humans, but that day is quite a ways off.

I bring this up not to detract from the science, but to point out how it has been portrayed to the public. I made the mistake of looking to the comment sections of these articles to find top comments such as “Oh my goodness, yes! This has happened IN my lifetime.” While I like to see people excited about research, a life in science has also trained me to be skeptical (and there were more realistic comments as well). Yet, it appears the articles gave some people premature hope by suggesting that the cure was already here.

As I read the paper and tried to translate the findings here, I can see the challenge that’s faced with disseminating science to the public. I dream of a day when the average person can pick up a scientific paper and understand its general idea, but until then, it’s the job of those reporting it to take this highly dense matter and do their best to accurately portray it, to make people excited but also aware of its limitations.

AIDS affects over 35 million people worldwide. Additionally, a large portion of the world is scientifically illiterate. Both are major problems in their own way and hopefully through effective journalism and research we will be able to mitigate them. It may not happen in my lifetime, but I must hope that some day it will happen.

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Image copyright: targovcom, thinkstock

Article last time updated on 13.07.2015.

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Leider ist die Zulassung von Ibrutinib bisher nur auf erfolglos vorbehandelte Kranke beschränkt. Wegen der weit überlegenen Wirksamkeit sowie geringer bekannter Nebenwirkungen möchte ich meine Patienten "Off label" damit behandeln. Würde diese Bahandlung von Krankenkassen übernommen? Immerhin kostet diese Therapie derzeit pro Jahr etwa 120.000,-€ Wie ist die Rechtslage?
#2 at 19.12.2014 from Dr.med Clemens S. Kretzschmar (Physician)
  1
Humberto E. Ferreira, FFUL, University of Lisbon, Portugal
As a pharmacist and an interested polymer scientist I see this piece of Genetic Engineering as a great breakthrough! Recent advances in finding vectors/vehicles that may transport the proteins that do the job, without hydrolysing and losing them, into the nucleus of the cell may help acelerate/speed the process of clinical use. Nano-particles of biodegradable polymers/plastics may be the solution here, especially if they can overcome the blood-brain barrier.
#1 at 05.09.2014 from Humberto E. Ferreira, FFUL, University of Lisbon, Portugal (Guest)
  1
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