Gene Editing for Cystic Fibrosis

Cystic fibrosis is caused by mutations in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Scientists are examining whether it is possible to correct the mutations through a process called gene editing.

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Summary
  • Gene editing uses the cell's own DNA repair machinery to correct the mutation in the cell's DNA.
  • The most versatile gene editing tool is called CRISPR. CRISPR is often preferred because it is inexpensive compared to other methods and is the easiest to customize.
  • A major advantage of gene editing is that the changes that it makes to the DNA are permanent. People might require only one treatment with a gene editing tool to have a lasting effect on their disease.

How Does Gene Editing Work?

A gene is a series of DNA letters that provides the instructions to build a protein. Because DNA is crucial to the cell, the cell has machinery to fix damage to its DNA. Gene editing uses the cell's own DNA repair machinery to correct the mutation in the cell's DNA. Unlike gene replacement therapy, gene editing corrects the mutations that are in the person's own DNA.

People with cystic fibrosis have a mutation in both copies of the cystic fibrosis membrane conductance regulator (CFTR) gene. To correct the CFTR mutations in someone's DNA, the tools needed for gene editing need to get inside the person's cells, which is very challenging.

Once the tool has gotten into the cell nucleus, the tool must then be able to find a series of about 20 DNA letters that mark the spot of the CFTR mutation out of three billion letters in the human genome. Then, the DNA needs to be broken right near the mutation in the CFTR gene.

Watch this video to see how this process might work.

Types of Gene Editing Tools

There are a few different tools that scientists have found that can locate a specific series of letters in the genome and break the DNA at that place. The most versatile gene editing tool is called CRISPR. CRISPR is often preferred because it is inexpensive compared to other methods and is the easiest to customize -- that is, it is easy to specify which series of DNA letters CRISPR will search for in the genome.

The CRISPR gene editing tools include a “guide” that locates the mutated sequence in the CFTR gene, a template with the correct segment of DNA letters, and “scissors” that break the patient's DNA at the site of the mutation.

Once the tools enter the cell and reach the mutated sequence of DNA, the scissors snip out the mutation. This damage attracts the attention of the cell's DNA repair machinery, which will then use the template to fix the break in the DNA. This permanently corrects the mutation in that cell. This gene editing process can repair one mutation at a time, or groups of similar mutations, depending on how the mutations are arranged in the DNA.

Watch this video to see how CRISPR/Cas9 editing works.

There are other tools that can be used for gene editing, including proteins called TALENs, meganucleases, and zinc finger nucleases. These all work in a similar way to CRISPR, but they are less popular because they are harder to customize and require a lot more time and expertise from researchers.

Challenges of Gene Editing for CF

A major advantage of gene editing is that the changes that it makes to the DNA are permanent. People might require only one treatment with a gene editing tool to have a lasting effect on their disease. However, many challenges still need to be overcome before gene editing can be used to treat CF.

For example, gene editing tools can be customized to find a specific CFTR mutation, but there are many CF-causing mutations. Researchers are studying the effectiveness and efficiency of different techniques in the lab that would allow the correction process to fix anywhere from one mutation to all mutations.

Off-site edits also pose a risk. In theory, gene editing should be a very precise therapy, meaning that the gene editing tool should break the person's DNA only at the site it was designed to find. For CF, the tool would be designed to find the site of the CFTR mutation.

In practice, gene editing is not perfect. Sometimes, gene editing tools break the DNA in the wrong place in the genome. An error like this could result in new mutations in other genes and cause unintended consequences, such as an increased risk for cancer. For this reason, each gene editing tool must be evaluated individually to determine whether it is precise enough to be used in patients.

Current gene editing technologies rely on the cell's own DNA repair machinery to fix the break in the DNA caused by the gene editing tool. However, the cell's DNA repair machinery can only complete its work if the cell undergoes a round of cell division (one cell dividing into two new cells). In an adult, a small population of airway stem cells regularly undergo cell division; however, most of the cells in organs like the lung do not divide. This could mean that gene editing would not be able to correct CFTR mutations in many lung cells unless the stem cells were specifically targeted. New technologies are being developed that might work even in cells that do not divide. These new technologies may allow gene editing to work in more cells in the lung.

Gene editing is an area of very active research and is nearing clinical trials for treating several diseases of the blood, such as sickle cell disease. These diseases are good targets for gene editing because blood cells can be taken out of the body and treated with gene editing tools in the laboratory. Once the gene editing tools have corrected the mutations, the blood cells can be returned to the body.

Treating a disease like CF that affects the lungs and other internal organs is much more difficult because it is very hard to get the gene editing tools into lung cells, a process called gene delivery. Gene editing for CF is currently being tested in cells and animals, and it will be a number of years before it can be safely tested in people.

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Topics
Genetic Therapies | Research
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