Cystic Fibrosis (CF) Gene Therapy Research
Cystic Fibrosis (CF) is due to genetic mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), which results in aberrant chloride ion transport. Defective chloride ion transport leads to chronic bronchiectasis, which is the driving cause for the morbidity and mortality in CF. While CFTR modulator drugs improve short-term pulmonary function, these drugs are only approved for 50 percent of CF patients with specific mutations. The approach of developing first-in-class and subsequent best-in-class small molecule CFTR correctors and potentiators are not an efficient approach to treat CF when there are over 2000 known specific mutations of CFTR. Further, current small molecule modulator drug compounds require daily administration and their annual costs approach 300,000 dollars due to the unique mutations and small subset of patients that have the specific mutation. Gene therapy would have a theoretical advantage over small molecule CFTR modulators because treatment would be universal regardless of the type of CFTR mutation. However, gene therapy efforts in the past for CF have achieved limited success.
Viral-based gene therapy was first attempted with adenovirus but the approach led to serious immunological toxicity and lack of efficient gene delivery. Adenovirus gene delivery is inefficient because the targeted CAR receptor is located on the bottom surface of the airway epithelium, which is not accessible by aerosol delivery. Gene therapy shifted towards the use of adeno-associated virus (AAV) because of its lower immunological toxicity. However, the major drawback of AAV is that the virus cannot package the full-length CFTR gene (~4.7 kb).
The United Kingdom CF Gene Therapy Consortium has initiated a clinical trial that involves aerosolizing a unique nonviral (plasmid-based) gene therapy. There has been no organized effort in the United States to test the efficacy and safety of virus-free, gene therapy in clinical trials. The major limitation of plasmid-based gene delivery has been its reduced efficiency. However, there has been little research conducted in the United States to improve plasmid-based gene therapy for CF. The Institute, along with a biopharmaceutical company, is developing an alternative nonviral gene therapy for CF. The research remains early in the preclinical phase. However, we are in need to recruit patients to obtain blood samples to test the potential efficacy of this treatment. Patients with CF are asked to sign up on our patient registry.
We are in need to recruit patients with CF and develop stem cell models that are representative of the patient's lung disease. The Institute is currently developing a diverse biorepository of CF-stem cell models for testing this gene therapy. For further details of the Institute's biorepository program, please go to that link.