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Cystic fibrosis is a hereditary disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes an ion channel protein that is involved in the transport of salts across cell membranes. Any of dozens of different mutations of the gene can lead to the development of cystic fibrosis.
The primary symptom of cystic fibrosis is a build-up of mucus in the lungs and other organs, leading to frequent infections and other complications. The lifespan of a person with cystic fibrosis is significantly shortened by the disease.
Gene therapy may offer a potential avenue for curing cystic fibrosis through the repair of the defective CFTR gene. The basic idea behind gene therapy is to deliver a functional copy of the gene to cells and program them to begin making the functional copies. There are many approaches to gene therapy, but the most common strategy is packaging the repair gene inside a virus, known as a vector, for transport into the cells. Viruses have evolved over millions of years to evade the immune system, attack cells, reprogram them and replicate their own genomes, so a virus is a logical candidate for transporting beneficial genetic material. For gene therapy, the virus is modified so that it is harmless, and the desired gene is packaged inside.
However, viral vectors have been hindered in delivering gene therapy for cystic fibrosis by the defense system of the lungs against infection. One strategy for improving the ability of viruses to deliver gene therapy to the lungs in cystic fibrosis comes from a collaboration between the UK Cystic Fibrosis Gene Therapy Consortium and DNAVEC, a Japanese biotech company. Researchers from the two groups modified a lentivirus with two proteins to increase the efficiency of transduction in the airway. Those vectors performed well in animal studies, and trials in humans are scheduled to begin in 2017.
In another recent study, researchers from the University of Edinburgh, Imperial College London, and other collaborators used a “bubble of fat” (liposome) instead of a virus to deliver the virus to the lungs. The treatment was administered through a nebulizer, and resulted in a 3.7 percent improvement in lung function compared to placebo. The modest improvement is considered a very encouraging sign that the researchers are on the right track.
An ongoing study at University College Cork is examining the question of whether the faulty CFTR gene can be repaired rather than replaced as in conventional gene therapy. In conventional gene therapy, an additional copy of the whole gene is delivered to cells and begins to function. However, the malfunctioning gene is still present and so the ‘fix’ offered by gene therapy is by nature partial.
The CFTR gene repair strategy cuts out a part of the gene containing the six most common mutations leading to cystic fibrosis (accounting for about 80% of all cases), and replaces the entire region with a normal sequence. The “patch” is delivered to cells by the same methods as conventional gene therapy, packaged with “cellular scissors,” or nucleases, that cut out the mutated region and replace it. The repair is then permanent and the cell behaves exactly like a healthy cell.
Gene editing is a technique closely related to gene therapy. Whereas in gene therapy a new, functional gene is transferred into the cells to replace a defective gene, gene editing works by repairing the defective gene at the DNA level. Operating at one level beyond CFTR gene repair, gene editing aims to “rewrite” the mutated sequence directly within the original gene, much like editing a sentence with spelling errors. Gene editing technology is still at a very early stage. Studies of gene editing in other diseases like cancer and HIV have shown promise and will soon be tested in clinical trials. The technique may also be successful with cystic fibrosis.