A transformational NanoNucleic delivery technology is being investigated by Savara Inc. as a promising first-in-class gene therapy candidate for lung cancer. A potent lung cancer therapy with fewer side effects is urgently needed due to the exceptionally high rates of morbidity and mortality of this particular cancer. Gene therapy, while promising, remains clinically unsuccessful, mainly due to insufficient therapeutic gene expression in cancer tissues, and adverse effects of the delivery vectors. Recently, a novel nanoparticle technology for nucleic acid delivery (""""""""NanoNucleic"""""""" technology) was developed at the University of Kansas, and licensed exclusively to Savara Inc, a drug development company specializing in the treatment of lung diseases. The NanoNucleic technology comprises a cationic peptide bundled with DNA (or RNA for siRNA delivery), and condensed by calcium into small nanoparticles (75-100 nm). Using the NanoNucleic technology, high local expression of endogenous apoptosis inducer genes (TRAIL and angiotensin II type 2 receptor (AT2R)) was achieved in the lungs of mice. Over-expression of either gene induced marked cell death in several human lung cancer cell lines in culture, but the effect on normal lung epithelial cells or fibroblasts was minimal. AT2R over-expression also induced significant cell death in lung cancer progenitor cells in culture. After administering an intratracheal spray o AT2R or TRAIL genes as NanoNucleic formulations to LLC mice, gene expression lasted at least two weeks. Observations of the treated lungs revealed a remarkable reduction in tumor burden, without any signs of toxicity toward the native tissue, nor signs of inflammation. Unlike viral vector-based gene therapy, NanoNucleic gene therapy is expected to generate minimal host immune response and none of the viral gene- associated drawbacks such as gene mutations or the production of oncogenes via random insertion into the genome.
The aim of the proposed research is to provide therapeutic proof-of- concept of an optimized form of NanoNucleic gene therapy approach using two different therapeutic gene candidates (AT2R, and TRAIL) in two different in vivo lung cancer models. NanoNucleic formulations will be administered intratracheally, with or without complementary intravenous administration. The strong preliminary data in the mouse LLC model suggest a high likelihood of success in this proposed Phase I research. Successful completion of the Phase I will enable advancement of the program into efficacy studies using K-ras gene mutation- and tobacco carcinogen-induced lung cancer models, as well as chronic safety studies in larger animals, and thereby build a solid foundation for eventual translational research.
The primary objective of this research is to develop a practical gene therapy for non-small cell lung cancer by developing a nanoparticle gene-delivery system. Treatment strategy proposed here is significantly better than existing therapeutic strategies since efficient therapeutic outcomes with fewer side effects are expected.
|Ishiguro, Susumu; Alhakamy, Nabil A; Uppalapati, Deepthi et al. (2017) Combined Local Pulmonary and Systemic Delivery of AT2R Gene by Modified TAT Peptide Nanoparticles Attenuates Both Murine and Human Lung Carcinoma Xenografts in Mice. J Pharm Sci 106:385-394|
|Alhakamy, Nabil A; Ishiguro, Susumu; Uppalapati, Deepthi et al. (2016) AT2R Gene Delivered by Condensed Polylysine Complexes Attenuates Lewis Lung Carcinoma after Intravenous Injection or Intratracheal Spray. Mol Cancer Ther 15:209-18|