PNA-based method is a key component of the gene editing toolkit

The Somatic Cell Gene Editing Consortium (SCGE) of the National Institutes of Health has given a comprehensive update on the status of their nationwide initiative to design safer and more effective techniques to edit the genes of disease-relevant somatic cells and thus minimize the burden of a disease induced by genetic changes.

Professor of Chemistry Danith Ly joined the National Institutes of Health’s Somatic Cell Gene Editing Consortium in 2019. Image Credit: Carnegie Mellon University.

The study was published in the Nature journal on April 8^th, 2021.

Gene editing, which enables researchers to alter the sections of an organism’s DNA, is seen as a potential treatment for many genetic diseases. Over the past few decades, there have been many advancements in laboratory settings, but despite this fact, there are still many obstacles to overcome before gene editing can be extensively applied to the patient population.

The SCGE, established in 2018, has brought together some of the field’s leading scientists to advance the discovery and speed up the translation of somatic gene editing developments from the laboratory to clinical settings.

Over the span of six years, the NIH will provide around $190 million to SCGE to understand the potential of gene editing. The final outcome will be a publicly available toolkit that will benefit the biomedical research community through rigorously assessed data about genome methods and editors for delivering and monitoring gene-editing molecules.

NIH realized it was important for all of us who are investigating gene editing to work together toward a common goal. We’re designing molecules that can go into the cell and we’re cataloging each and every one. What we’ll end up with is a very valuable, rigorously evaluated resource for those who want to bring gene editing to patients.”

Danith Ly, Professor, Chemistry, Carnegie Mellon University

Professor Ly joined the consortium in 2019.

Although much of the consortium’s research work targets CRISPER-Cas-related systems, the SCGE underscored the importance of the sustained development of other systems. They specifically pointed out the peptide nucleic acid-based gene editing method designed by Professor Ly from Carnegie Mellon University and Peter Glazer from Yale University.

“Although there is a significant focus on CRISPR-Cas related systems within the SCGE, it is crucial to continue to explore alternate systems, in part because they may differ in both their potential for delivery and their biological or immunological responses,” the consortium wrote in the Nature journal.

CRISPR-Cas-related systems edit genes in cells that have been eliminated from the body, but the peptide nucleic acid (PNA) method developed by Professor Ly and Glazer is intravenously administered and it edits cells in vivo.

With the help of nanoparticles, a PNA molecule combined with a donor DNA strand is directly transmitted to a malfunctioning gene. As a leading scientist in synthetic nucleic acid research, Professor Ly has programmed the PNA molecules to open double-stranded DNA at the location of a targeted mutation.

The donor DNA from the complex attaches to the faulty DNA of the cell, triggering the DNA’s inherent repair mechanisms to modify the gene. This technique was used by the team to treat beta-thalassemia in adult mice as well as in fetal mice in utero.

The PNA gene-editing system lacks the high yield of the CRISPER-Cas systems but it is less likely to off-target modifications, which is a major advantage. This means that the new approach could be better for treating genetic diseases where only a small percentage of cells need to be corrected to make a therapeutic difference, added Professor Ly.

In the beta-thalassemia research works, for instance, Professor Ly and Glazer discovered that editing only 6% to 7% of cells was curative.

Professor Ly and Glazer have planned to refine and develop their method by participating in SCGE, and they are looking ahead to share their findings with the consortium and the larger biomedical community.