Delivering Gene Therapy To Lung Using Nanoparticles

Ever since the gene responsible for cystic fibrosis was discovered 25 years ago, scientists have envisaged gene therapies to correct the underlying genetic defect.

Today, gene therapies are being tested in clinical trials at centers across the country, including the Gunnar Esiason Cystic Fibrosis Lung Program at Columbia University Vagelos College of Physicians and Surgeons. But their success may be hindered by the difficulty of delivering therapies to an organ that is highly complex and made less accessible by the disease itself.

Gordana Vunjak-Novakovic, a pioneering biomedical engineer at Columbia, spoke with us about new devices and nanoparticles her lab is developing to improve the delivery of gene therapies to the lung and bring new treatments to patients with cystic fibrosis and other lung diseases.

Can you tell us about gene therapy for cystic fibrosis?

Cystic fibrosis is caused by mutations in the gene that encodes the CFTR protein, which maintains the balance of salt and water in the epithelial cells that line the lung. When CFTR is mutated, it malfunctions and causes abnormally thick mucus to collect in the lungs, which can lead to serious bacterial infections and severe lung damage. This lung disease usually leads to early death in people with cystic fibrosis.

The gene therapies that are currently in clinical trials use a harmless adenovirus to introduce copies of a corrected CFTR gene into the lung's cells, so that the cells can make fully functional CFTR proteins.

Gene therapy could potentially be a better treatment for cystic fibrosis than current therapies because it could permanently repair the cells that are causing the disease by delivering a corrected CFTR gene. Ideally, gene therapy would be administered before the lung becomes significantly affected with fibrotic changes.

What's the catch?

The treatments currently being tested are made into an aerosol, which is inhaled by the patient. In small animal models, this approach can be effective at delivering the corrected gene to the lung's epithelial cells and improving the clearance of mucus.

"For cystic fibrosis patients, the therapy needs to cross the thick mucus caused by the disease."

One big question is whether this mode of delivery can be effective in human lungs, which are incredibly complex. From the upper airway to the alveoli (the tiny air sacs deep within the lungs), the lungs branch 24 times, with each branch getting smaller and smaller. It's very difficult to distribute therapeutic drugs, genes, or cells throughout the lung, and in a way that is minimally invasive. For cystic fibrosis patients, the therapy also needs to cross the thick mucus caused by the disease.

Do you have a solution?

We're investigating the use of nanoparticles that are just billionths of a millimeter in size to carry their therapeutic cargo deep into the lungs. To enhance and better control gene delivery we're developing ultrathin catheters with optical fibers that are delivered with imaging guidance and regional ventilation. This kind of treatment can be effective, comfortable for the patient, and repeated multiple times, as needed. Such an approach would greatly facilitate delivering new therapies that are being tested at Columbia.

We teamed up with people outside of the engineering lab to develop these technologies. Dr. Emily DiMango, who runs the cystic fibrosis center at Columbia, is guiding us in tailoring our approach to the specific needs of people with cystic fibrosis.

Which brings us to another aspect of your work: creating models of the lung for research.

With a Pioneer grant from the Cystic Fibrosis Foundation, we are developing a whole lung model that is bioengineered to replicate the properties associated with cystic fibrosis, including the presence of mucus. This model allows us to test new treatments, like gene therapies, under precisely controlled conditions and to observe their effects on cells and tissues in real time.

To this end, we are combining our cross-circulation platform, which maintains ventilation and perfusion in the lung outside of the body, with the introduction of bioartificial mucus and an array of methods for monitoring and evaluating therapeutic delivery and the changes in lung function.

Another thrust of your research is how to increase the supply of lungs for transplantation. Could you tell us about this work?

For many patients with end-stage lung disease, the only treatment option is a lung transplant. Unfortunately, there's a huge shortage of viable donor organs. Only about 20% of donor lungs, which are already in short supply, are suitable for transplantation.

If we could recover rejected or marginal-quality donor lungs, that would radically change the prognosis for thousands of patients.

Over the last 10 years, we were supported by the National Institutes of Health to study how to rejuvenate less-than-ideal donor lungs by removing the injured epithelium-the site of most lung damage-while preserving all of the supporting tissues, including the lung matrix and blood vessels. These denuded areas can then be repopulated by epithelial progenitor cells, derived from adult induced human pluripotent stem cells, to enable lung regeneration. The result, we hope, will be a functional chimeric human lung that meets transplantation criteria.

Additional information

Gordana Vunjak-Novakovic joined the Columbia faculty in 2005. She holds the academic rank of University Professor and is the first engineer at Columbia to receive this highest distinction. She is also the Mikati Foundation Professor of Biomedical Engineering and Medical Sciences (in medicine) and director of the Laboratory for Stem Cells and Tissue Engineering.