Infectious diseases: CTRL + ALT + Delete
Gene editing is revolutionizing the bioscience research landscape and holds great promise for “deleting” diseases from human bodies. Sandia National Laboratories is working to make this technology safer and to ensure that one day it can be delivered into humans without triggering adverse immune system reactions or causing other undesirable side effects.
Sandia biochemist Joe Schoeniger explains that gene editing technology is based on a “billion-year-old arms race” between bacteria and the viruses trying to attack them.
Bacteria save bits of invading viral DNA using a system called Clustered Regularly Interspaced Short Palindromic Repeats or CRISPR. This system helps bacteria recognize a virus when it returns for a repeat attack. The CRISPR system produces Cas9, an enzyme that binds to the offending viral DNA, then cuts and destroys it.
This bacterial defense system can be programmed. Scientists can send CRISPR-Cas9 to a precise location to alter a specific bit of DNA.
The ability to alter DNA is useful, especially when dealing with genetic diseases, but alterations to DNA are currently irreversible. Using the technology as it is today could cause unintended, dangerous and permanent side effects. It could cut a genome in the wrong place (i.e., have off-target effects), potentially causing disease.
In addition, CRISPR-Cas9 needs a carrier to be delivered into human cells. Typically, this carrier is a virus linked to the common cold called adeno associated virus. According to Sandia virologist Oscar Negrete, a majority of people have been exposed to strains of this virus at some point. This means people are quick to manufacture antibodies against it, making it a one-time use only therapy. Even on that first use, patients are likely to have an immune reaction, Negrete explained. New approaches are needed that enable the treatment to be successfully used more than once if necessary.
Controlling CRISPR
To be able to control CRISPR technology and use it without causing permanent DNA changes, the Defense Advanced Research Projects Agency created the Safe Genes program.
One effort being funded under Safe Genes is a $2.5 million, two-year project led by Jennifer Doudna’s laboratory at the University of California, Berkeley, in partnership with Sandia, and the University of California, San Francisco. Doudna is a pioneer in the development of CRISPR. If the early research is fruitful, DARPA could extend this effort for another two years, bringing the total to four years and $5 million.
Viruses are skilled at changing their DNA and generating new anti-CRISPR proteins to block the bacterial immune systems. This is the other side of the bacteria-virus “arms race.” These proteins can function as antidotes, allowing gene editors to be turned off if needed.
The Safe Genes team is taking advantage of these proteins to develop inhibitors that can control off-target effects of CRISPR. Schoeniger said that should a dose of a gene editor need to be administered, it could be followed by a dose of the inhibitor to shut it off, minimizing the amount of time in which off-target effects could take place.
