Gene therapy: a promising candidate for cystic fibrosis treatment
An improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment. Those are the encouraging results of a study presented by the Laboratory for Molecular Virology and Gene Therapy at KU Leuven, Belgium.
Cystic fibrosis or mucoviscidosis is a genetic disorder that makes the mucus in the body thick and sticky, which in turn causes clogging in, for instance, the airways and the gastrointestinal tract. The symptoms can be treated, but there is no cure for the disorder.
Cystic fibrosis is caused by mutations in the CFTR gene. This gene contains the production code for a protein that functions as a chloride/bicarbonate channel and regulates fluid secretion across the epithelium in different organs (airways, pancreas, intestine, sweat glands and vas deferens). In the cells of CF patients, these chloride channels are dysfunctional or even absent, so that thick mucus starts building up. Persistent airway infections are the major clinical manifestation. Gene therapy holds promise to cure the disease. Previous studies suggested that the treatment is safe, but largely ineffective for CF patients. However, as gene therapy has recently proven successful for inherited disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for cystic fibrosis.
Here we developed an improved gene therapy treatment based on inserting the genetic material for chloride/bicarbonate channels – coded by the CFTR gene – into the genome of a recombinant AAV viral vector, which is derived from the relatively innocent AAV virus (Fig. 1). We used this vector to transfer a healthy copy of the CFTR gene into the affected cells. We administered the therapeutic vector to CF mice via their airways. Most of the mice recovered. In patient-derived intestinal cell cultures, chloride and fluid transport was restored.
Development of CF gene therapy requires a thorough preclinical examination of a candidate vector in relevant cell and animal models before being administered to humans. Here, both in mice with CF and in mini-guts or intestinal organoids derived from CF patients, this approach yielded positive results. We still have to examine how long the therapy works. Repeated doses might be necessary to ensure a prolonged therapeutic benefit. Also, our candidate gene therapy product will have to be validated in a larger animal model that develops clear lung pathology as seen in CF patients to evaluate its potential to prevent or cure lung disease. This would be a crucial step towards the development of a gene-based treatment for CF.
We believe that our study will revive the interest in CF gene therapy research, but we must not give CF patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis.
Drs. Dragana Vidović, Marianne Carlon and Professor Dr. Zeger Debyser
Laboratory for Molecular Virology and Gene Therapy
KU Leuven, Belgium
rAAV-CFTRΔR Rescues the Cystic Fibrosis Phenotype in Human Intestinal Organoids and Cystic Fibrosis Mice.
Vidović D, Carlon MS, da Cunha MF, Dekkers JF, Hollenhorst MI, Bijvelds MJ, Ramalho AS, Van den Haute C, Ferrante M, Baekelandt V, Janssens HM, De Boeck K, Sermet-Gaudelus I, de Jonge HR, Gijsbers R, Beekman JM, Edelman A, Debyser Z.
Am J Respir Crit Care Med. 2016 Feb 1
|The flipside of cystic fibrosis protein transport Deficiency of ATP8B1 in humans causes severe progressive liver disease that is characterized by impaired bile flow. Besides liver disease, many ATP8B1 disease patients develop extrahepatic symptoms of yet unknown…|
|Structure and function of the esophageal mucosa Structure and function go hand-in-hand amongst the morphology, morphometry, biomechanics and secretory potential within the alimentary tract mucosa, submucosa and muscularis propria. Structure must evolve first during the development of…|
|Cyagen Biosciences – Helping you choose the right… While many animal models are available “ off the shelf ” through various repositories and collaborations, generation of novel animal models has allowed for more effective studies, not limited by…|
|The role of monocytes in ANCA-associated vasculitides The anti - neutrophil cytoplasm antibody (ANCA) - associated vasculitides (AAV) include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). These rare systemic autoimmune diseases affect small and medium - sized…|
|Building and rebuilding gastric epithelium: Trop2 as… In mammals, the stomach is lined by a contiguous layer of cells called epithelium, further organized into units called glands. Gastric glands are divided into two areas: corpus and antrum,…|
|How does histamine make it hard to breathe? Histamine is a chemical substance that can be released in the lungs to cause narrowing of the bronchial tubes and difficulty breathing. Airway smooth muscle cells in the bronchioles (small…|