CRISPR to the RESCUE: Gene Editing Technology Gets More Versatile

The Context: CRISPR is a powerful gene editing tool which traditionally works by locating and modifying stretches of DNA within the genome. However, this technique creates a permanent change. Base editing is a technique that changes RNA (which is transcribed from DNA) rather than DNA itself, allowing for temporary edits. Current base editing technology can only target one type of mutation, however, so its use is limited.

The Study: Researchers from MIT led by NYSCF – Robertson Stem Cell Investigator Dr. Feng Zhang report in Science that they have developed a new CRISPR-based tool, called “RESCUE”, which expands the capabilities of base editing by allowing it to target a wider range of disease-causing mutations. The team successfully used RESCUE to change an Alzheimer’s risk gene into a benign form.

The Importance: RESCUE is a safer and more versatile version of CRISPR which will help researchers learn more about the genetic basis of disease and potentially serve as an effective therapeutic.

An update to the gene editing tool CRISPR is making the technology safer and more versatile as well as opening the door for further study and treatment of neurodegenerative diseases like Alzheimer’s.

Feng Zhang, PhD, a NYSCF – Robertson Stem Cell Investigator and MIT Professor of Biological Engineering who pioneered the use of CRISPR in human cells, and his team unveiled the new base editing technology, deemed “RESCUE” (RNA Editing for Specific C to U Exchange), in a study published in Science last week.

What is base editing?

Base editing technology such as RESCUE allows researchers to make temporary changes to the genome by editing RNA rather than DNA. Some mutations in DNA lead to disease because they alter the function of RNA or proteins that are produced by DNA. To repair these effects, one option is to correct the mutation in the DNA, as traditional CRISPR does. Another approach is to correct the RNA through base editing. Correcting RNA means the change is more short-lived — a more desirable option for certain therapies than making a permanent change to the human genome.

Additionally, while traditional CRISPR makes its edits by cutting strings of bases, which can sometimes result in potentially harmful ‘off-target’ effects, base editing techniques like RESCUE target single bases. This reduces the chances of cells acquiring unintended changes.

What is special about RESCUE?

Until now, base editing could only correct A (adenosine) to I (inosine, the equivalent of guanine) mutations through a system called REPAIR (also developed by Dr. Zhang’s lab). The RESCUE system uses an ‘enzyme’ that can target C (cytosine) and change it to U (uracil). This significantly widens the scope of disease-causing mutations CRISPR can repair.

“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” said Dr. Zhang in a press release from MIT.

How will RESCUE help us understand and treat brain disease?

By expanding the range of disease mutations that can be corrected using base editing, RESCUE provides a powerful tool for researchers to study the basis of brain disease and to potentially treat some of these diseases. In this study, Dr. Zhang’s team demonstrated this by using RESCUE to correct a gene variant, APOE4, that puts carriers at risk for late-onset Alzheimer’s disease. By making two C-to-U swaps, the researchers were able to turn APOE4 into the more benign variant APOE2, which is not a risk factor.

Read more in Fierce Biotech and Technology Networks

Original Journal Article:

A cytosine deaminase for programmable single-base RNA editing.
Abudayyeh OO, Gootenberg JS, Franklin B, Koob J, Kellner MJ, Ladha A, Joung J, Kirchgatterer P, Cox DBT, Zhang F. Science. 2019. doi: 10.1126/science.aax7063.