Worldwide, more than 30,000 individuals are living with cystic fibrosis (CF) and each year, around 1,000 new cases of CF are detected. Cystic fibrosis is a severe genetic condition brought about by a faulty gene known as CFTR (cystic fibrosis transmembrane conductance regulator). The gene makes a protein that controls the water and salt movement within the body. In individuals with cystic fibrosis, this gene is defective and causes an abnormal buildup of thick and sticky mucus. This mucus, in turn, can cause characteristic signs and symptoms of cystic fibrosis such as wheezing, shortness of breath, recurrent infections, and other complications.
Cystic fibrosis is a hereditary disease, meaning an individual with cystic fibrosis is a carrier of two copies of the altered gene – one from each parent. When two carriers of CF have a child, the odds are:
- 25% that the child will have cystic fibrosis
- 50% that the child will be a carrier but will not have cystic fibrosis
- 25% that the child will not be a carrier and will not have cystic fibrosis
Statistics show that more than 75% of individuals with CF are diagnosed by the age of 2 and more than half of the CF patient population is aged 18 or older. Currently, research is underway to substitute the faulty gene with a functioning one through means of gene therapy. The general idea behind gene therapy is to deliver a functional gene to bodily cells and program them to act accordingly and multiply into practical copies. Previous attempts using a type of virus to transport the functioning gene were proven unsuccessful as the lung’s defense mechanism worked against the infection and prevented the virus from entering.
In a new study, researchers from Imperial College London, Oxford, and Edinburgh Universities, NHS Lothian and the Royal Brompton & Harefield NHS Foundation Trust, came together to create a gene therapy on behalf of the Cystic Fibrosis Trust. They developed a new technique that would permit patients to breath in DNA molecules in order to deliver a common copy of the faulty gene to the cells in their lungs. The researchers used a bubble of fat instead of a virus to reach the lungs. The treatment was administered in 136 patients through a nebulizer, their lung functions were measured, and the results showed a 3.7% increased progression in lung function. “It is the world’s first demonstration that repeated gene therapy can improve lung function. The effects were modest and variable. This is not yet ready for clinical use for those reasons” said Professor Eric Alton, the coordinator of the UK Cystic Fibrosis Gene Therapy Consortium from Imperial College.
The effectiveness of frequent dosing
Half of the patients treated at both the Royal Brompton Hospital in London and at Western General Hospital in Edinburgh were given gene therapy and the other half was given saline. Individuals who showed greater improved results were those with the most terrible lung function to begin with. Professor Alton explained that the mucus was damaging the smaller airways, for which reason the dose resulted in the superior airways. Researchers dosed the patients once a month and noted that frequent dosing could improve results. In a larger clinical trial, they would try to join gene therapy with other treatment methods and measure the ending results.
Although the initial study presented several advantages and the results were encouraging, it did have its limitations.
- The study was relatively small, engaging with 136 patients. A larger clinical study needs to be conducted in order to fully assess the results of the effectiveness and safety of this type of therapy.
- The study took into account clinically stable patients with cystic fibrosis at their most favorable respiratory health. Therefore, as to how exactly gene therapy would work in clinically unstable patients remains unknown.
A second trial is being planned to deliver gene therapy through a specifically engineered virus. Professor Alton notes that if the following trial is successful, it could have a major impact on improving lung function for CF patients by 2020 and preventing initial lung damage. Yet, developing a gene therapy for cystic fibrosis nowadays has proven to raise difficulties. “The lungs must be one of the worst possible organs to go for. They are so extremely well-defended. With bone marrow you can take it out, do the gene transfer in controlled conditions in the laboratory and put it back in the patient. That is the low-hanging fruit. We have gone for the high-hanging fruit but I’m not at all sorry we have” Alton said.
The cystic fibrosis trial was funded by the Medical Research Council and the National Institute for Health Research. George Freeman, Government’s Life Sciences Advisor said “Cystic fibrosis can have a devastating effect on patients and families and this is an excellent development for people living with the condition.” Furthermore, Ed Owen, Chief Executive of the Cystic Fibrosis Trust said “This is an extraordinary time for therapeutic development in cystic fibrosis and the need is urgent to stop so many young lives being cut short because of this cruel condition. We will therefore continue to invest in innovative genetic research and to work with academic and industry partners to develop advancements which will make further progress towards our goal of a life unlimited by cystic fibrosis.”
The results of the trial showed improvement in lung capacity for the children and adults who took part in the trial. However, it is important to note that both groups’ lung function worsened over the year, as the treatment remained limited. The gene therapy was able to lessen some of the gene deterioration, yet not all of it. Nevertheless, researchers believe that gene therapy is a possibility for treating cystic fibrosis and concluded that “although we are encouraged by the first demonstration of a significant beneficial effect in lung function compared with placebo associated with gene therapy in patients with cystic fibrosis, the mean difference was modest, only recorded in some individuals, and at the lower end of the range of results seen in clinical trials which result in changes in patient-related care.” They added “further improvements in efficacy and consistency of response to the current formulation, or its combination with CFTR potentiators, are needed before gene therapy is suitable for clinical practice.”
In 2012, the United States Food and Drug Administration (FDA) approved the first drug to target the main defective gene associated with CF. Shortly thereafter, the FDA approved the second drug to treat the root cause of cystic fibrosis. Today, the next steps in the treatment process involve optimizing the dose for gene therapy and testing it in several other patient groups. While gene therapy is definitely a breakthrough in modern medicine, plenty of experimentation and clinical trials need to be conducted before it can become an available treatment option to be used on a regular basis. With more work, researchers hope that this type of treatment will become available within 5 years’ time and at least be a possibility in helping to stabilize patients with cystic fibrosis. What’s more, several research organizations are beginning to develop lifesaving new therapies for larger patient groups with CF, hoping to tackle the disease from every aspect.