Gene Therapy for Cystic Fibrosis

Cystic fibrosis is caused by mutations in the gene responsible for producing the cystic fibrosis transmembrane conductance regulator (CFTR) protein. For this reason, scientists are exploring ways to provide a correct copy of the gene to treat CF.

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Summary
  • In integrating gene therapy, a piece of DNA that contains a correct version of the CFTR gene would be delivered to an individual's cells. The new copy of the CFTR gene would then become a permanent part of their genome.
  • In non-integrating gene therapy, a piece of DNA with a correct copy of CFTR is provided to an individual's cells, but the DNA remains separate from the genome.
  • RNA therapy would deliver a correct copy of the RNA to the cell.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene contains the instructions for making the CFTR protein. When there is a mutation -- or alteration -- in the genetic instructions, the production of the CFTR protein may be affected. In people with cystic fibrosis, mutations in the CFTR gene can result in no protein, not enough protein, or a protein being made incorrectly. Each of these defects leads to a cascade of problems that affect the lungs and other organs.

Since the discovery of the CFTR gene in 1989, scientists have been trying to find ways to correct the mutations in the gene that cause CF. Although progress was initially slower than anticipated, scientific breakthroughs in the past 10 years have accelerated advances in gene therapy, also known as gene transfer or gene replacement.

Gene therapy is a process in which a new, correct version of the CFTR gene would be placed into the cells in a person's body. Although the mutant copies of the CFTR gene would still be there, the presence of the correct copy would give cells the ability to make normal CFTR proteins.

Watch this animation to see how this might work.

Gene therapy has shown significant promise not just for people living with cystic fibrosis, but for other genetic diseases. In this video, Mitch Drumm, PhD, a professor at Case Western Reserve University, answers questions from the CF community about what the future of gene editing could look like for CF. 

An advantage of gene therapy is that it could work in any individual with CF, no matter what mutations the person has. A disadvantage of gene therapy is that it can work only in cells that receive the therapy. That means that if gene therapy is used to treat the lungs, it will not help the cells in the digestive system.

Gene therapy cannot repair organ damage that has already occurred. Although gene therapy could reduce the symptoms of CF and prevent further damage from occurring, it cannot fix scarring or other permanent damage that happened prior to the treatment. 

Here we will explain three types of gene therapy and the potential they have to treat CF. It is not yet clear which option will work best. The process of physically delivering gene therapy technology to cells is full of challenges. These obstacles would have to be overcome for any gene therapy to work.

Integrating Gene Therapy

In integrating gene therapy, a piece of DNA that contains a correct version of the CFTR gene would be delivered to an individual's cells. The new copy of the CFTR gene would then become a permanent part of their genome, which is the entire set of genetic instructions that is in every cell. This kind of gene therapy is similar to binding a new page into an existing book.

An advantage of an integrating gene therapy is that it is permanent. This means that a person with CF might have to receive the gene therapy only once or a few times in his/her life. A disadvantage is that we may have limited control over where the new copy of the CFTR gene integrates into the genome. The new copy could be inserted into a part of the genome that contains some critical information, like the new page being randomly added to a book and disrupting an important chapter. This means integrating gene therapy could have undesirable side effects, such as increasing the risk of cancer.

A type of integrating gene therapy, known as CAR-T therapies, has already been approved to treat patients with certain kinds of leukemia and lymphoma. An integrating gene therapy to treat CF is being tested in animals, and a clinical trial to test the safety of this therapy in people with CF could happen in the next several years.

Non-Integrating Gene Therapy

In non-integrating gene therapy, a piece of DNA with a correct copy of CFTR is provided to an individual's cells, but the DNA remains separate from the genome. This is like placing a new page between the covers of an existing book without permanently attaching it. Even though the gene therapy does not become part of the genome, the cell can still use the new copy of the CFTR gene to make normal CFTR proteins.

A major advantage of this approach is that the non-integrating gene therapy does not disrupt the rest of the genome, just like adding a new page right under the cover of a book would not disturb the contents of the rest of the book. That means that the risk of side effects, including cancer, is low. A disadvantage of non-integrating gene therapy is that it is not permanent. Because of this, the effect of the gene therapy might last only for several weeks or months. A person with CF would probably need to be treated with the gene therapy repeatedly for it to be effective.

Non-integrating gene therapy has now been approved by the U.S. Food and Drug Administration (FDA) to treat a rare type of blindness, and it has also been shown to work in studies for hemophilia, a blood clotting disorder. It has also been tested in people with CF. In a clinical trial in England, people with CF were given a dose of a non-integrating gene therapy once per month for a year. The study indicated that the CF gene therapy was safe and resulted in a small improvement in lung function.1 Additional work is needed to improve this kind of gene therapy so that it will be more effective at treating CF.

RNA Therapy

Genes are composed of a series of DNA “letters” that spell out the instructions to make a protein. However, the cell does not use the DNA directly. Instead, the cell makes a working copy of the gene using a similar alphabet called ribonucleic acid (RNA) and uses that working copy to build the protein. Both integrating and non-integrating gene replacement therapies involve giving DNA copies of the CFTR gene to a cell and letting the cell make its own RNA working copies. But, another approach is just to give the cell the RNA copies directly.

Watch this video to see how this process might work.

The advantage of RNA therapy is that there is no risk of disrupting a person's genome. Using RNA also makes it easier to control the dose.

A disadvantage is that the effects of the RNA therapy might last only for a very short time, such as one or two weeks. This would mean that a patient would have to get repeat doses of the therapy to see improvements.

RNA therapies are being developed to treat a wide range of diseases. A potential RNA therapy for CF is being tested in an early-stage clinical trial to determine safety.

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