Our DNA is like a book that contains the instructions for building and operating our body. Sometimes, however, there are errors in this book that can cause disease. Can we “correct” these errors as we do with a text editor, modifying only what is wrong? It is no longer just a hypothesis: First Medicines ha announced on May 19 that a teenager with a rare immune disease has been given the world’s first treatment with prime editing, a gene-editing technique that allows faulty DNA sequences to be rewritten with surgical precision. And the initial results are surprisingly positive.
The disease and the results of the treatment Prime editing
The boy suffers from a disease called chronic granulomatous disease, a dangerous condition that disables several immune cells, especially neutrophils. This disease makes the body unable to adequately fight bacteria and fungi, leading to serious and potentially fatal infections.
Researchers designed a treatment to correct the genetic mutation responsible for the disease. One month after the therapy, the teenager had no serious side effects. But there's more: the function of a crucial enzyme was restored in about two-thirds of his neutrophils, a value well above that needed to provide a significant boost to the immune system.
It’s too early to know if the treatment has been successful: it will take six months to a year to be sure the modified stem cells are thriving.
These words Annarita Miccio, who studies gene therapy at the Imagine Institute of the Necker Children's Hospital in Paris. Although she is not involved in the research, she adds that it is a promising approach to treat a complex disease, and that Prime Medicine's previous results in mice were encouraging.
What is prime editing?
But what makes this technique special? Prime editing is considered the most versatile member of the CRISPR family, the famous “genetic scissors” that have revolutionized biotechnology in recent years.
While traditional CRISPR-Cas9 works a bit like a “cut and paste” system, prime editing acts more like a sophisticated “search and replace,” allowing specific segments of DNA to be rewritten with greater precision. As we anticipated, this technique allows “not only to correct letters, but to rewrite entire sentences in the DNA book, inserting or deleting sequences with surgical precision”.
Prime editing, essentially, combines the powerful scanning and sequence-finding capabilities of the CRISPR-Cas9 system with an enzyme called reverse transcriptase, which uses an RNA template to synthesize a new DNA sequence and insert it into the genome.
Advantages over traditional CRISPR
Compared to traditional CRISPR-Cas9 technology, prime editing offers several advantages. Two, mainly. The first: does not create double-stranded cuts in DNA, which can be dangerous and lead to unwanted changes. This makes the technique potentially safer.
The second: can introduce a wider range of changes (substitutions, small insertions, and deletions) with greater precision and flexibility. This makes it suitable for correcting a wider variety of mutations responsible for genetic diseases.
It's like upgrading a smartphone. There are new versions coming out all the time and the tools are constantly being improved.
This is the metaphor used by Joseph Hacia, a medical geneticist at the Keck School of Medicine at the University of Southern California in Los Angeles, to describe the evolution of genome editing techniques.
The future of therapy
Despite these early signs of success, Prime Medicine has announced that it will not further develop the therapy, called PM359, on its own. The decision reflects the harsh realities of developing gene-editing therapies for very rare diseases.
The only gene-editing therapy currently on the market is a CRISPR-Cas9-based treatment for two blood disorders, sickle cell anemia , beta-thalassemia. This therapy costs more than $2 million per dose and has faced a slow launch process in the US and UK.
However, the testing on PM359 will continue. In 2023, the FDA has authorized the application for an investigational new drug (IND) for PM359 for the treatment of chronic granulomatous disease, making PM359 the first primary editor to enter the clinic.
Conclusion
This first successful use of prime editing in a human patient represents a historic moment for genetic medicine. As these technologies mature, we could see more effective, cheaper (mostly. Hopefully), and safe treatments for a wide range of genetic diseases.
The path to widespread application of these therapies will likely be long and complex, with challenges related to cost, access, and ethical issues. But this first step demonstrates that we are entering a new era of precision medicine, where “proofreading” our genetic code could become a viable option for many currently incurable diseases.
