Much has been made of CRISPR gene editing over the past decade or so. An incredibly effective method for snipping and altering targeted sections of DNA, CRISPR began as a two-part molecular tool that sets extremely precise edit points on the genome and then cuts entirely through DNA in order to make advantageous changes to it.
The CRISPR gene editing process has made extraordinary steps forward in the treatment of genetic diseases that were previously untreatable. And the potential of this technology seems to be virtually endless!
For better or for worse, however, conventional CRISPR makes permanent changes to DNA that may be unnecessarily complicated or have unanticipated consequences. This is even more concerning in light of the fact that CRISPR-altered DNA will be passed down to future generations in perpetuity.
But a new, modified version of CRISPR’s basic architecture called “CRISPRoff” promises to sidestep these problems by making alterations to the epigenome rather than the genome itself. Leaving the genome uncut and entirely intact, CRISPRoff dramatically furthers the editorial reach of CRISPR gene editing while offering enhanced control and eliminating many safety concerns.
Unlike the genome, which is composed of DNA in and of itself, the epigenome encompasses the chemical compounds and biological proteins that tell the genome precisely what to do. These compounds and proteins attach to DNA and conduct actions that include turning specific genes on or off, thereby controlling the building blocks of cellular activity.
Developed by a team of research scientists at the University of California San Francisco (UCSF) and the Whitehead Institute, CRISPRoff can switch off most human genes, without editing the genetic code. This team demonstrated that any gene that is turned off will remain off for up to 450 generations unless it is subsequently turned back on using another new tool, which is aptly named “CRISPRon.”
Both the CRISPRoff and CRISPRon processes begin by using only the component of conventional CRISPR gene editing that sets edit points on the genome. Rather than subsequently cutting the genome at these edit points to splice DNA, CRISPRoff and CRISPRon tether an enzyme to these points that act only on the epigenome.
In other words, CRISPRoff can target specific genes and stop them from activating the problematic cellular protein production that leads to various genetic diseases such as cystic fibrosis. As UCSF researcher and co-senior author of the CRISPRoff project Luke Gilbert puts it, “Though genetic and cellular therapies are the future of medicine, there are potential safety concerns around permanently changing the genome, which is why we’re trying to come up with other ways to use CRISPR to treat disease.”
Although it leaves the genome entirely whole and unaltered, CRISPRoff technology can protect patients from diseases by making molecular changes that are just as permanent as conventional CRISPR gene editing. Unlike conventional CRISPR, however, the changes made by CRISPRoff are fully reversible thanks to the development of CRISPRon.
Essentially, CRISPRoff and CRISPRon can turn a gene off and on like a light switch. This is a giant step forward from conventional CRISPR gene editing, which is akin to removing and replacing the entire lighting apparatus permanently and in its entirety.
Cystic fibrosis is only one of many diseases that clinical professionals can potentially treat using CRISPRoff. Patients with rare genetic disorders that range from the connective tissue disorder Marfan syndrome to the immune system disorder Job’s syndrome may soon benefit from CRISPRoff technology.
Scientists also see tremendous promise for CRISPRoff when it comes to the treatment of many types of cancer. It is important to note, however, that further work is necessary to realize CRISPRoff’s full therapeutic value.