Non-viral systemic delivery of siRNA or antisense oligonucleotides targeted to Jun N-terminal kinase 1 prevents cellular hypoxic damage

Many pathological conditions and environmental impacts lead to the development of severe tissue hypoxia that aggravates the primary disorder, provokes cell death, and limits the patient's recovery. We hypothesized that suppression of Jun N-terminal kinase 1 (JNK1) will limit tissue damage induced by severe hypoxia. To test the hypothesis, antisense oligonucleotides (ASO) or small interfering RNA (siRNA) targeted to JNK1 mRNA were incorporated or complexed with neutral or cationic liposomes, respectively, and administered systemically to mice prior to hypoxia exposure. The animals were placed in a special chamber ventilated with room air (normoxia) or a gas mixture containing 6% O-2 and 94% N-2 (hypoxia). Liposomes, ASO, and siRNA were found to accumulate in the lungs, kidney, spleen, and heart. Only trace amounts of liposomes and their payloads (ASO and siRNA) were found in the brain. The down regulation of JNK1 protein limited activation of cell death signal, apoptotic, and necrotic tissue damage under hypoxic conditions. Consequently, we were able to verify our hypothesis and provide proof of concept of a unique approach to the prevention of cellular hypoxic damage by the suppression of JNK1 signaling pathways after the efficient delivery of ASO or siRNA.