Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide

Abstract

The last years have shown enormous advancement in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, leading to increased numbers of ASO regulatory approvals. In this study we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease, Cystic Fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when aiming to target the cell nucleus. The efficient distribution of SPL84 in the lungs, penetration into the cells and nucleus, and stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate the proper distribution and cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability and mobility of our inhaled ASO drug through CF patient-derived mucus and in lung lysosomal extracts. Our results, supported by a promising pre-clinical pharmacological effect, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 and specific cell targeting offers huge opportunities for further development of SpliSense inhaled ASO-based drugs for unmet pulmonary diseases.