Pig Model of Cystic Fibrosis Seen to Aid in Development of Gene Therapies

Two studies published in the Journal of Clinical Investigation (JCI) demonstrate the potential of pigs with cystic fibrosis (CF) — the ExeGen CFTR miniswine model — to test the effectiveness and workings of gene therapies for the disease. This animal research model was developed by Exemplar Genetics, a subsidiary of Intrexon Corporation.

CF is caused by mutations in the CFTR gene, which contains the coding information for a protein with the same name. When dysfunctional, this protein contributes to the accumulation of mucus in several organs, including the lungs, promoting bacterial growth and infection.

The ExeGen CFTR pigs carry a mutation in the CFTR gene that causes the loss of function of the protein, mimicking the disease in humans. The researchers believe that these pigs provide an appropriate model for the development of CF therapies, given that pigs have greater anatomical, physiological, and genetic similarity to humans than other animals. Also, the CF pigs develop lung disease in a similar way to CF patients.

The first study, titled “Lentiviral-Mediated Phenotypic Correction Of Cystic Fibrosis Pigs,” was carried out by Ashley Cooney, with the University of Iowa, and colleagues. The team used a lentiviral gene delivery therapy, a technique that uses a modified virus capable of entering cells and introducing a copy of a gene in a cell’s DNA, but without causing a viral disease. This technique allows the correction of a genetic defect — in this particular case,  the correction of the CFTR gene. Results showed that the gene delivery was successful, and that pigs showed signs of functional activity of the CFTR protein, as well as reduced bacterial infection and improved overall health.

The second study, “CFTR Gene Transfer With AAV Improves Early Cystic Fibrosis Pig Phenotypes,” was conducted by Benjamin Steines, with the University of California, and colleagues. Researchers used the adeno-associated virus (AAV), a virus that uses the machinery of the infected cells to produce new copies of their genetic information, again without causing a viral disease. In this case, the AAV virus was used to introduce copies of the normal CFTR gene in the airways of the CF pigs. The team observed that pigs receiving this therapy not only had functional CFTR expression in their airways, but also stronger defenses against bacterial infection.

The ExeGen CFTR pigs were used in a previous study to test the effectiveness of small molecules in the treatment of CF. That study was also published in the JCI.

Exemplar has other genetically modified pig models for use in the study of other diseases, such as heart disease, cancer, cardiac arrhythmia, neuromuscular disease, and neurodegenerative disease.

“We are pleased our models are attracting the attention of leading academic and commercial researchers by providing a powerful investigational platform, enabling better predictive efficacy in the generation of innovative therapies that translate from bench to clinic,” said John Swart, PhD, president and chief executive officer of Exemplar Genetics, in a news release.