期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8720-8725
DOI：10.1073/pnas.1502281112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTherapeutically relevant lung gene therapy is yet to be achieved. We introduce a highly translatable gene delivery platform for inhaled gene therapy based on state-of-the-art biodegradable polymers, poly({beta}-amino esters). The newly designed system is capable of overcoming challenging biological barriers, thereby providing robust transgene expression throughout the entire luminal surface of mouse lungs. Moreover, it provides markedly greater overall transgene expression in vivo compared with gold standard platforms, including a clinically tested system. The clinical relevance is further underscored by the excellent safety profile as well as long-term and consistent transgene expression achieved following a single and repeated administrations, respectively. Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly({beta}-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.
