Scientists Develop New Gene Editing Approach Capable of Gene-Sized Insertions

Rare Daily Staff

Scientists at UMass Chan Medical School have unveiled a new gene editing approach that could significantly expand the scope of genetic medicine by enabling the insertion of large, gene-sized DNA sequences into the human genome.

The technology, dubbed “prime assembly,” combines elements of prime editing and Gibson assembly to allow researchers to replace extended stretches of DNA—potentially entire genes—rather than making small, targeted edits. The work, published in Nature, represents a step toward addressing genetic diseases caused by numerous mutations scattered across a single gene.

Current gene editing tools such as CRISPR-Cas9, base editing, and prime editing are typically limited to modifying short DNA sequences, often just a few dozen base pairs—akin to changing a single letter or word in a book. Prime assembly, by contrast, enables researchers to rewrite much larger sections.

“It’s like replacing an entire paragraph or chapter in our genetic book,” said Wen Xue, professor of RNA therapeutics and co-senior author of the study.

The system can insert DNA sequences as large as 11,000 base pairs—approaching the size of full genes—potentially allowing a single therapeutic strategy to correct many different mutations within a patient population. This could be especially impactful for genetic diseases in which hundreds of distinct mutations exist, making individualized editing approaches impractical from both development and regulatory standpoints.

Technically, prime assembly builds on a twin prime editing strategy that creates complementary DNA flaps at the target site. These flaps guide the insertion of donor DNA without introducing double-strand breaks, which are commonly used in CRISPR-based editing but can lead to unintended mutations. Instead, the method relies on single-strand nicks, which are generally considered less disruptive to cells.

Another advantage is its ability to function in nondividing cells, such as neurons, broadening its potential therapeutic applications to neurological disorders. The approach also allows multiple DNA fragments to be stitched together, mirroring the capabilities of Gibson assembly used in laboratory settings.

“This is a substantial step forward, not just because of the length of the DNA sequences we were able to insert, but also because of how relatively streamlined the process is,” said Erik Sontheimer, vice chair and professor of RNA therapeutics at UMass Chan.

The research team included collaborators from UMass Chan and The Ohio State University, and the authors say future work will focus on understanding the cellular mechanisms underlying the technology and advancing it into animal models.

If successfully translated, prime assembly could mark a shift toward more universal gene therapies capable of addressing complex genetic disorders with a single, scalable platform.

UMass Chan Scientists Erik Sontheimer and Wen Xue – photo by Bryan Goodchild