Endobronchial Gene Delivery for Pulmonary Hypertension in a Large Animal Model.

Pulmonary hypertension (PH) is a devastating disease with high morbidity and mortality. Despite significant progress in the pharmacotherapy, current treatments only ameliorate the symptoms and cannot heal PH. Gene therapy may target the roots of the disease and holds evident promise. The current bottleneck for lung gene therapy is the delivery method. The requirements for the delivery mode are efficiency, safety, and the ability to target the anatomical site of interest, while avoiding off-target effects. Aerosolized gene delivery has been used in several studies and proven to be an efficient mode of administration for lung gene therapy. In this chapter, we describe a protocol of endobronchial aerosolization for PH gene therapy in a large animal model. Testing of a gene therapy in large animals is essential before clinical testing, since the lung anatomy and (patho)physiology differ immensely between humans and rodents, where most of the proof-of-concept studies are tested. The gene delivery vector is being aerosolized in the peripheral bronchi using a sprayer inserted through a flexible bronchoscope. This delivery mode results in efficient lung uptake and less off-target distribution relative to other airway delivery methods.