Next-Gen CRISPR Boosts Accuracy in Gene Therapy

Making Gene Editing More Precise

Until recently, genetic modifications were rather crude, inserting a new genetic sequence randomly into the target organisms.

The method of insertion was also very destructive. As a result, only bacteria and plants would be routinely genetically modified, and any gene editing in organisms like mammals (including humans) was complex, expensive, and slow.

This has partially changed with CRISPR technology, which suddenly opened the way for precise and controlled gene editing, resulting in the first gene therapy for human genetic disease being approved at the end of 2023.

However, CRISPR is still not perfect, sometimes resulting in unwanted genetic modifications.

This might have just changed with a breakthrough discovery from three MIT researchers.

They announced a new method allowing radically improved gene editing reliability, opening the way for creating new therapies.

They published their results in the prestigious scientific review Nature¹, under the title “Engineered prime editors with minimal genomic errors”.

From Standard CRISPR To Prime Editing

Since the approval of the first CRISPR-Cas9-based therapies, the idea of reliably editing the genomes of patients to cure them is no longer science fiction. However, CRISPR technology is not always modifying the targeted gene the way the scientists intend it to.

The CRISPR system consists of an enzyme called Cas9 that can cut double-stranded DNA at a particular spot, along with a guide RNA that tells Cas9 where to cut.

Researchers have adapted this approach to cut out faulty gene sequences or to insert new ones, following an RNA template.

Since 2019, MIT researchers have published a new concept called prime editing, which is more precise than regular CRISPR-Cas9 gene editing. As a result, it has fewer off-target effects and less chance of causing extra health problems to often already weak patients.

Prime editing uses a modified Cas9 fused with a reverse transcriptase enzyme, allowing it to perform all possible genetic base modifications, as well as small insertions and deletions of genetic sequences.

So in the long run, prime editing is expected to become the upgraded and more reliable version of CRISPR-based gene editing.

Source: Benjamin McLeod

For example, prime editors were successfully used in 2025 to treat a patient with chronic granulomatous disease (CGD), a rare genetic disease that affects white blood cells.

“In principle, this technology could eventually be used to address many hundreds of genetic diseases by correcting small mutations directly in cells and tissues.”

Vikash Chauhan – MIT’s Koch Institute for Integrative Cancer Research

But it needed a bit of improvement before being ready to use in people’s cells & bodies.

How Prime Editing Improves DNA Insertion Accuracy

Prime editing cuts just one of the complementary strands of the target DNA sequence, opening up a flap where a new sequence can be inserted.

Once the new sequence has been copied, however, it must compete with the old DNA strand to be incorporated into the genome.

If the old strand outcompetes the new one, the extra flap of newly created DNA hanging off may accidentally get incorporated somewhere else, giving rise to errors.

Such errors could ultimately cause cancer by inserting itself randomly in the genome, a clear risk that needs to be reduced.

With the most recent version of prime editors, this error rate ranges from one per seven edits to one per 121 edits for different editing modes, which is still too high.

“The technologies we have now are really a lot better than earlier gene therapy tools, but there’s always a chance for these unintended consequences,”

Vikash Chauhan – MIT’s Koch Institute for Integrative Cancer Research

Major Leap in Prime Editing Reliability

In 2023, the MIT researchers discovered that some mutated versions of the Cas9 protein used in prime editing would sometimes make their cut one or two bases further along the DNA sequence, instead of always in the same spot.

This made the old DNA strands less stable, so they get degraded, making it easier for the new strands to be incorporated without introducing any errors.

In this new 2025 study, the researchers have identified multiple Cas9 mutations that identify Cas9 mutations that dropped the error rate to 1/20th its original value.

When combining these mutations artificially all in one Cas9 protein, they dropped the error rate to 1/36th of the original amount.

“This paper outlines a new approach to doing gene editing that doesn’t complicate the delivery system and doesn’t add additional steps, but results in a much more precise edit with fewer unwanted mutations,”

Phillip Sharp – MIT’s Koch Institute for Integrative Cancer Research

Not content with doing that, they also used a prime editing system that has an RNA-binding protein that stabilizes the ends of the RNA template more efficiently.

Dubbed vPE, the final version of their gene editing toolkit had an error rate just 1/60th of the original, or only  101-543 edits, depending on the editing modes used.
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The Next Steps

Another hurdle of gene editing has always been delivering the gene editing proteins and DNA/RNA inside the nucleus of the targeted cells, or targeting only specific tissues in the body.

So this will be the next focus of the researchers, especially as prime editing techniques are limited by poor delivery compared to smaller and simpler “traditional” CRISPR-Cas9 systems.

They also think this tool has the potential to speed up progress in biotech overall, not just for gene editing therapies.

First, the technique and discovery that modification of the Cas9 protein can improve its reliability could be deployed to all CRISPR-based gene editing technologies, not just prime editing.

Second, this could become a powerful boost to other research projects using gene and genome editing as a research tool. For example, finding answers about how tissues develop, how populations of cancer cells evolve, and how cells respond to drug treatment.

“Genome editors are used extensively in research labs.

So the therapeutic aspect is exciting, but we are really excited to see how people start to integrate our editors into their research workflows.”

Vikash Chauhan – MIT’s Koch Institute for Integrative Cancer Research

Lastly, the mutations found to improve Cas9 reliability might not have been all found in this study. So further analysis and optimization of this new concept could yield even better results in the future.

Investing in Gene Editing

Illumina

While the other -omics in multiomics (proteomics, transcriptomics, etc.) are important, almost all articulate one way or another around genomics, the core “instruction manual” of every living cell.

And by far, the largest producer of genome sequencing machines is Illumina. The company is focused on short genetic sequence reading, which is the one used for cancer detection. It currently has 22,000+ installed sequencers in 165 countries.

Around half of Illumina’s sequencing machines’ consumables are used in clinical applications, with the other half used in public and private research labs. In clinical applications, half of the demand comes from oncology.

Source: Illumina

As genomics and multiomics become the center of the drug discovery process, as well as cancer diagnostics, Illumina’s equipment is expected to be in high demand.

The company expects the demand for NGS (Next Generation Sequencing) to grow by 18% CAGR for clinical applications and 6% CAGR for research, boosting the sector’s total addressable market (TAM) from $100B for clinical and to $25B for research by 2033.

Source: Illumina

Illumina had a complicated history with liquid biopsy company Grail (GRAL -0.36%), which was a spin-off from Illumina, later reacquired, and now forced back into a spin-off by competition authorities in the US and the EU.

With this trouble out of the way, Illumina might resume its long-term growth and stock price rise, especially as, ultimately, Grail’s liquid biopsy tests will likely still rely on Illumina sequencers.

Meanwhile, more gene therapies will also increase the use of Illumina’s sequencers in both research and clinical settings.

(You can also read a more detailed analysis of Illumina’s business, future technologies, and history in the dedicated investment report.)

Latest Illumina (ILMN) Stock News and Development

Study Referenced

^{1. Chauhan, V.P., Sharp, P.A. & Langer, R. Engineered prime editors with minimal genomic errors. Nature (2025). https://doi.org/10.1038/s41586-025-09537-3}