Gene editing in genetic medicine

This week a new company, BEAM therapeutics, was launched. It hopes to use a recent gene editing technique, known as base editing, to make therapies for genetic diseases. It is another exciting example of the huge potential of gene editing in genetic medicine.


What is gene editing?

Gene editing describes technologies used to change DNA by adding, removing or replacing letters of code, which are called bases. Gene editing techniques have been around for many years, but there has been an explosion of innovation over the last five years. This is mostly due to the advent of CRISPR techniques. CRISPR methods are simpler, cheaper, more versatile, more efficient and more scalable than most other gene editing systems.


Most gene editing systems cut DNA

The simplest CRISPR systems work by combining an enzyme that cuts DNA, (such as Cas9), together with a RNA guide that targets the DNA break to a specific place in the genome. The DNA break switches on mechanisms that repair broken DNA. One of these, non-homologous end joining (NHEJ), glues broken DNA ends back together, but it isn’t very accurate. At the join there are often base insertions or deletions that cause the gene to stop working. Check out our blog on different mutation types to find out why indels (the collective term for insertions and deletions) stop genes working. This simple use of CRISPR is very useful if switching off a particular gene is all you need to do.

But often we want more control over how the gene is edited. We can make use of a different DNA repair mechanism, known as homology-directed repair (HDR), to help do this. HDR uses a template to show how the break should be repaired. HDR is more accurate than NHEJ, but happens less efficiently. So it is not possible to force all the DNA breaks to be repaired by HDR.

This ‘molecular scissor’ type of gene editing has advanced many areas of science, in humans and other organisms. But it has limitations as a gene therapy approach. You can get cuts where you don’t want them (off-target effects), the correction rates are low, the rate of unwanted indels is high, and you can’t do precise edits of one base to another base.


Base editing rewrites DNA

Base editing is a newer form of gene editing that was developed a few years ago. This type of gene editing doesn’t start with a double-strand break so doesn’t have the problems of error-prone DNA repair by NHEJ. Base editing is more direct and more precise. It lets you change a single, specific DNA base to a different base, with high efficiency.

Base editing still uses a RNA guide to bind enzymes like Cas9 to DNA, but the Cas9 is altered so that it doesn’t cut the DNA. Instead, at the target site a specific base (e.g. A) is replaced with another base (e.g. G). It is prevented from being repaired back again by an inhibitor that is part of the base editing unit. Meanwhile, the modified Cas9 nicks the unedited strand which prompts the cell to repair it, but instead of being complementary to the old base (T) it is repaired so it is complementary to the new base. So you end up with a perfect swap on your double helix of A:T to G:C.


Gene editing is useful for variant interpretation

One of the potential applications of gene editing in genetic medicine is to improve variant interpretation, which is a major bottleneck. At the moment, we wait until a gene variant is found through genetic testing to evaluate it’s impact. This makes interpretation slow, and for many variants we don’t have a way of testing their impact. Gene editing gives us an opportunity to generate gene variants at large-scale and test their impact in the laboratory. As long was we know what impact to test for.

For example, Jay Shendure’s team has used a technique called saturation genome editing to investigate the impact of nearly 4000 variants in BRCA1. They looked to see which of the variants have the same disease-causing profile as BRCA1 variants known to be disease-causing. To do this they used cells that can only survive if BRCA1 is working properly. Disease-causing variants in BRCA1 cause these cells to die, because they stop BRCA1 working. They tested which of the 4000 variants caused the cells to die – these are likely to be disease-causing variants. And which variants didn’t cause the cells to die – these are almost certainly benign variants. We could use similar approaches for many other disease genes. They would would help reduce the number of ‘variants of uncertain significance’, making variant interpretation faster and more accurate.


Gene editing will transform gene therapy

Gene editing has potential to deliver cures for devastating diseases.

One of the most exciting applications of gene editing is in gene therapy. Base editing will be particularly useful because many genetic diseases are due to a single base change. Base editing also has lower off-target effects and much lower rates of indel generation.

We still need to do a lot more research and we will need to overcome many challenges. But, we will likely see clinical trials using treatments based on gene editing within the next ten years.


Societal considerations

There are many, many ways in which gene editing will be beneficial for science and medicine. As with any transformative technology there is also potential for consequences that concern society. Or for misuses of the technology that cause harms. We will need to discuss this openly and ensure that the appropriate safeguards are in place so gene editing research can flourish. We have a tool with the potential to cure devastating diseases and we should do everything we can to make that happen.