Cystic fibrosis (CF) is a rare, heritable disease caused by mutations in the CFTR gene, which provides instructions for making the CFTR protein. This protein normally forms a channel at the membrane of cells for the transport of salts in and out of the cell. In CF, this channel is either not present, or fails to open because of mutations, which leads to the buildup of sticky mucus in different organs and tissues.
What is gene therapy?
Gene therapy is an approach that is intended to replace a faulty gene with a healthy one. To make a protein from a gene, the DNA sequence of the gene is used as a template to make a temporary copy. This is called a messenger RNA (mRNA). This mRNA is used as the template by the cellular machinery of the cell to make the protein. A mutation in a gene causes the mRNA to be made with an error, or it could prevent the gene from being copied into mRNA.
The ultimate goal of gene therapy for CF is to replace the faulty CFTR gene with a healthy copy of the gene. There are three broad types of gene therapy currently being explored as CF treatments.
Integrating gene therapy
Integrating gene therapy is a treatment that introduces a normal copy of the disease-causing gene that is integrated into the genome of the patient. Current therapies are using delivery methods such as a liposome (a particle made with an artificial fat membrane), a harmless virus, or a nanoparticle that delivers a piece of DNA to cells. Once inside the cell, the DNA piece has to be integrated into the genome. One strategy for doing this is using the CRISPR/Cas9 system.
Once integrated into the genome, the healthy copy of the gene is able to code for a normal protein. This type of treatment would be permanent; however, the therapy will only work on the cells that are treated. If the treatment is administered to the lungs, for example, then the heart or gastrointestinal tract will not be treated. Moreover, the gene that is being integrated can potentially insert anywhere, even in the middle of another gene and cause unforeseen problems. Researchers want to be sure that gene therapy will not cause additional problems for patients before it can be tested in the clinic.
Non-integrating gene therapy
Non-integrating gene therapy is a treatment that delivers a healthy copy of the gene to the cell, but the DNA does not become part of the genome. The gene is expressed normally but is not copied when the cell divides, so it is not a permanent treatment and patients would have to continue receiving treatment throughout their lives. As with integrating gene therapy, this type of therapy would only affect the cells that are treated.
Instead of treating cells by introducing the gene and letting them make their own mRNA copies, RNA therapy involves giving cells mRNA from which to make the protein directly. Using RNA therapy makes it easier to control the dose of the therapy, but patients would have to receive treatments more frequently than with other types of gene therapy. MRT5005 is an example of this type of therapy.