A Gene Editing Approach to Work Across Multiple Diseases

Rare Daily Staff

Researchers at the Broad Institute have developed a new genome-editing strategy that could potentially lead to a one-time treatment for multiple unrelated genetic diseases.

Gene-editing medicines are often made one at a time to treat a specific mutation, an approach that is difficult to scale up to address the thousands of rare diseases affecting patients around the world. The new technology, called PERT (prime editing-mediated readthrough of premature termination codons), is designed to maximize the potential of gene editing by using just one editing agent to serve as many patients as possible.

David Liu, director of the Merkin Institute of Transformative Technologies in Healthcare and vice chair of the faculty at the Broad Institute of MIT and Harvard, led the research, which was published in a study in Nature.

PERT uses prime editing—a DNA editing system developed by Liu’s lab in 2019—to rescue a type of mutation that can cause about a third of rare diseases. These so-called “nonsense mutations” can occur in many genes and cause cells to stop synthesizing their associated proteins too early, resulting in truncated, malfunctioning proteins that can lead to disease.

Normally, when a cell needs to make a protein, it first transcribes DNA into mRNA. Other molecules called tRNAs then read the mRNA sequence and bring the corresponding amino acid building blocks together into a chain that becomes the final protein. A special three-letter sequence in the mRNA—UAA, UAG, or UGA—marks the end of the protein assembly instructions. This signal is called a termination codon.

Genetic diseases caused by nonsense mutations create an errant termination codon somewhere in the middle of the mRNA sequence. This causes the cell to halt protein production too early. Liu’s team sought to develop a universal way to permanently equip the cell to overcome these premature termination codons, allowing protein synthesis to continue as normal. The researchers hope the approach can provide a single, one-time gene-editing treatment that benefits patients with different diseases caused by nonsense mutations.

The PERT approach does not directly edit these nonsense mutations—a strategy that would require developing a different editing agent for each mutation—but instead makes another edit that equips cells with a tool to produce the normal, functional version of the protein, regardless of which gene is impacted.

In the Nature paper, the team described how they tested PERT in human cell models of Batten disease, Tay-Sachs disease, and Niemann-Pick disease type C1, and in a mouse model of Hurler syndrome. The technology restored protein production and alleviated disease symptoms, with no detected off-target edits, changes in normal RNA or protein production, or toxicity to the cells.

“We hope this research will eventually pave the way for a clinical trial of PERT, and will inspire other broadly applicable, disease-agnostic gene-editing strategies,” said Liu. “If you don’t have to target one mutation at a time, the size of the patient groups that could be treated with a single drug becomes much, much larger. We hope the result will be many more patients that benefit, as well as greater incentives to develop gene-editing drugs for rare diseases.”