What is Gene Editing?
DNA, the genetic material inside every cell, is like an instruction book that tells our bodies how to function. Each gene, or unit of DNA, provides instructions to build one specific protein that does a specific job in our body. Mutations are changes in the DNA sequence that can affect these genetic instructions. If a gene contains a mutation, the protein might not work correctly or might not be made at all.
Gene editing refers to the use of targeted molecular tools to make specific changes to DNA inside cells. Gene editing tools can cut, remove, insert, replace, and fix specific DNA sequences. These changes to the DNA are then made permanent by the cell’s DNA repair machinery.
Because it can make changes to DNA, gene editing can be used as a therapy to fix disease-causing mutations. People with cystic fibrosis have a mutation in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Researchers are working on several gene editing approaches that could target and correct CFTR mutations.
It’s important to note that gene editing is different from gene therapy (also called gene transfer or gene replacement), which delivers a new copy of a gene but does not change a person’s original DNA.
How Does Gene Editing Work?
There are many types of gene editing proteins that can edit DNA. One of the most well-known gene editors is CRISPR-Cas9. Here’s an example of how CRISPR-Cas9 can work:
- Find the target: CRISPR-Cas9 uses a small piece of RNA, called a guide RNA, to guide the CRISPR-Cas9 to the exact spot in a gene that contains a mutation.
- Make a cut: CRISPR-Cas9 acts like scissors, making a deliberate cut at the target spot in the DNA.
- Repair the cut: The cell notices the cut in the DNA and starts to repair it. A healthy piece of the gene is provided so that the cell can use it as a template during the repair.
- Permanent results: After the repair, the formerly mutated DNA now contains the correct instructions to make the desired protein. This change is permanent.
Watch this video to see a visual example of CRISPR-Cas9 gene editing.
Precision vs. Efficiency
To work well, a gene editor needs to be both precise and efficient.
- Precision means making the exact desired change at the correct spot in the DNA, like hitting a target directly in the bullseye.
- Efficiency means changing the DNA in lots of cells, like hitting a target many times.
There are many types of gene editors, and they vary in precision and efficiency. The original version of CRISPR-Cas9 cuts all the way through the double helix of DNA. Scientists call this a double-strand break. Repairing a double-strand break as described in the example above is precise, but it is not very efficient.
Newer gene editing methods like base editing and prime editing use different versions of Cas proteins. Like CRISPR-Cas9, these newer approaches still use guide RNAs to find their target; however, they only cut one strand of the DNA. These single-strand breaks can be repaired through processes that are both precise and efficient.
Other gene editing proteins, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), and meganucleases, do not use guide RNAs. These proteins can directly locate, bind, and cut DNA without a guide RNA.
Early Success in Other Diseases
Scientists are still studying gene editing for CF in research labs, but for other diseases, it’s already being used to correct DNA mutations in people. In 2023, the FDA approved a gene editing therapy for sickle cell disease, a genetic disease that causes red blood cells to become misshapen. This approach uses gene editing to correct a patient’s cells outside of the body. When the cells responsible for making blood cells are returned to the patient, they can survive, work normally, and help reduce disease symptoms.
Other gene editing therapies are being tested in clinical trials. Researchers have seen early success for diseases including transthyretin amyloidosis (ATTR), chronic granulomatous disease (CGD), and alpha-1 antitrypsin disorder (A1AT), to name a few. In February of 2025, researchers treated an infant with the rare genetic urea cycle disorder CPS1 with a personalized type of gene editing called base editing therapy. Baby KJ received three doses of the therapy delivered intravenously to cells in his liver. Baby KJ is doing well so far, and his story has reshaped how many experts think about developing and testing gene editing therapies.
Because it is new, scientists are still very careful with gene editing, and trials may progress slowly. For example, baby KJ will require lifelong follow-up due to the severity of his condition and the type of treatment he received. The government has created rules about how gene editing can be used. Along with the scientific and medical community, they want to make sure gene editing is safe and fair for everyone.
Challenges of Gene Editing for CF
Many research labs have published evidence demonstrating precise and efficient correction of CF-causing mutations in cells and models. However, many challenges still need to be overcome before gene editing can be used as a therapy to treat people with CF.
Delivery
One of the biggest challenges of treating a multi-organ disease, like CF, is getting a therapy inside the right cells in the body, a process called delivery. Gene editing has worked well for blood diseases like sickle cell because blood cells can be taken out of the body. Scientists can remove a patient’s blood cells, treat them with gene editing tools in the laboratory, and return the edited cells to the body.
CF affects the lungs and other internal organs, which are harder to reach. For CF, a gene editor would need to be delivered directly to cells inside of the body. Right now, CF scientists are focusing on delivering therapies to the lung, because that is one of the organs most severely affected by the disease. Getting a therapy into lung cells is a big challenge because of the body's natural defenses to block germs and other foreign invaders from entering cells. Different delivery methods would be needed to target other organs affected by CF, such as the intestine or pancreas.
Cell Targeting
Human lungs contain many different types of cells that do different jobs, and most of them do not make CFTR protein. In order to be effective, genetic therapies need to make it inside the cells that do make CFTR protein. The cells that line the airway and make CFTR protein are called differentiated epithelial cells.
One challenge is that these cells have a limited lifespan in the body. Even though gene editing changes the DNA in a cell permanently, the edited cells will eventually die, and the changes will be lost. As lung epithelial cells die, they are slowly but continuously replaced by new cells. The new cells come from special cells called basal stem cells.
If a gene editing therapy can be delivered into basal stem cells, then all the new cells they make will contain the corrected DNA. That means people with CF might require only one or a few treatments with a basal stem cell-targeting gene editor to have lasting improvements in their CF-related lung symptoms.
Efficiency
Many gene editing tools rely on the cell's own DNA repair process to fix the DNA after it's been cut. However, these repair processes are more efficient in some cells than others. For example, DNA repair is usually more active in cells that regularly divide (one cell dividing into 2 new cells). In adults, the lung cells that make CFTR protein do not regularly divide, so some gene editing tools don’t work well in these cells. CF researchers are prioritizing newer gene editing technologies, including prime editing and base editing, that could work efficiently in all types of lung cells.
Off-target Edits
In theory, gene editing should be a very precise therapy, meaning that the gene editor should change a person's DNA only at the exact site it was designed to find. To treat CF, a gene editor would be designed to find a specific mutation within the CFTR gene. Because sequences of DNA throughout the genome can look similar to one another, gene editors will sometimes change the DNA in the wrong place. An error like this could create new mutations in other genes and cause unintended consequences, such as an increased risk of cancer. For this reason, scientists must carefully test each targeted gene editor in the lab to determine whether it is precise enough to be developed as a therapy for people.
One Disease, Many Mutations
Gene editors can be designed to find and fix a specific CFTR mutation, but there are hundreds of different mutations that cause CF. Developing a therapy for a single mutation is difficult if there aren’t enough people with that mutation to run a traditional clinical trial. Because many CF mutations are very rare, scientists are working on gene editing tools that could fix several mutations — or even all of them — with just one treatment.
One example is the “super-exon” approach. Researchers are studying specific proteins, that can move whole genes from one place to another in the genome. They hope to use these proteins to insert a full or partial copy of the CFTR gene into a person’s own DNA. If successful, this approach could benefit more than 99% of people with CF.
The field of gene editing is moving quickly. CF scientists have demonstrated successful correction of the CFTR gene in the laboratory. However, turning this lab technology into a treatment is challenging, and we are working diligently overcome the remaining hurdles — including getting a gene editing therapy into the right cells and finding a dose that is both safe and effective. Clinical trials are still several years away, but ongoing research gives real hope that gene editing could one day provide a lasting benefit – and potential cure - for people living with cystic fibrosis.
To explore the genetic therapy programs currently in development for CF, visit our Drug Development Pipeline.
For more detailed information on CRISPR-based gene editing research and applications outside of cystic fibrosis, we recommend CRISPRpedia, an educational resource produced and maintained by the Integrative Genomics Institute.
