Lung-targeting delivery of small interfering RNA for pulmonary therapeutics

About This Grant

Nucleic acid-based interventions have shown incredible growth over the last several years, especially with the advent of mRNA-based vaccines and new siRNA therapeutics. While this new class of medicine represents revolutionary progress, several shortcomings have been identified. Nucleic-acid based vaccines and their delivery systems can be highly-inflammatory. This may be advantageous in the context of vaccine applications, but can detrimental for therapeutics that require repeat administration, especially for inflammatory diseases. Systemically administered RNA interventions are largely hepatotropic, making effective targeted tissue delivery difficult outside of the liver. Without specific tissue or cellular targeting, many disease states remain impossible to address either because the nucleic acid intervention cannot reach the target efficiently or, if delivery is non- specific, lead to dose-limiting off-target effects. The lung, for example, is a highly desirable target for nucleic acid delivery for the litany of conditions that remain without treatment, such as acute respiratory distress syndrome/acute lung injury (ARDS/ALI), pulmonary hypertension, and fibrosis. However, a highly inflammatory drug substance would result in severe adverse effects due to the delicate nature of the organ. These disadvantages highlight the need for further research and development of nucleic acid carriers that can be formulated to reach specific tissues and cells where they can deliver payloads with surgical precision. Tiba’s approach to non-viral RNA delivery exploits a proprietary delivery system that is a potent alternative to current state-of-the-art lipid nanoparticles (LNPs). This chemical delivery platform, RNABL™, employs a unique RNA nanoparticle carrier technology based on dendritic aminoalkyl-branched lipidoids. Tiba Biotech has developed an extensive library of novel delivery materials and formulations that enable efficient extrahepatic delivery and avoid dose-limiting inflammatory effects that present a challenge to traditional LNP-based systems. Unlike competing polymeric systems, Tiba’s platform is also fully biodegradable and molecularly defined. The project proposed here aims to further advance the therapeutic application of a subset of RNABL delivery materials that exhibit highly specific siRNA transfection in lung tissue when administered intravenously. Preliminary studies have established that endothelial cells are the primary site of uptake, and transfected siRNA can alter protein expression when using these optimized formulations, making them an appealing target site of action for novel vasoprotective biologic treatments. To meet the need for improved, lung specific nucleic acid carriers, we proposed a three-part, in vivo project to: 1) identify the optimal RNABL formulation for selective siRNA delivery to lung endothelium; 2) test the knockdown potency of leading candidates targeting CD31 expression in the lung; and 3) determine the clinical potential of this knockdown approach using an LPS ARDS/ALI mouse model targeting a known mediator of disease progression, NOX4.