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Idiopathic Pulmonary Fibrosis (IPF) Drug Development Using SAMiRNA, a Second-Generation RNAi Platform Technology
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A1636 - Idiopathic Pulmonary Fibrosis (IPF) Drug Development Using SAMiRNA, a Second-Generation RNAi Platform Technology
Author Block: P. Yoon; Bioneer Corporation, Daejeon, Korea, Republic of.
RATIONALE: SiRNA silencing approach has long been used as a method to regulate the expression of specific target gene in vitro and in vivo. However, the effectiveness of delivery and the nonspecific immune stimulatory function of siRNA are the limiting factors for therapeutic application of siRNAs. METHODS: To overcome limitations in in vivo delivery of siRNA, we developed self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticles made of individually bi-conjugated siRNA with hydrophilic polymer and lipid on their ends and characterized their stability, immune stimulatory function and in vivo silencing efficacy. RESULTS: SAMiRNA form very stable nanoparticles with no significant degradation in the size distribution and polydispersity index over 1 year. Overnight incubation of SAMiRNA on murine PBMC did not cause any significant elaboration of innate immune cytokines such as TNF-α, IL-12 or IL-6, while unmodified siRNA or, liposome or liposome complex significantly stimulated the expression of these cytokines. Lastly, in vivo silencing efficacy of SAMiRNA was evaluated by targeting amphiregulin (AR) in bleomycin or TGF-β transgenic (Tg) animal models of pulmonary fibrosis. Only two or three times of intratracheal (i.t.) or intravenous (i.v.) delivery of AR SAMiRNA significantly reduced the bleomycin- or TGF-β-stimulated collagen accumulation in the lung and substantially restored the lung function of TGF- β Tg mice. CONCLUSION : SAMiRNA is a safe, stable and effective platform for silencing disease-associated genes, useful in therapeutic applications for IPF and various fibrotic diseases. Currently we are developing a First-in-class IPF RNAi drugs through Non-clinical toxicology studies.
Author Block: P. Yoon; Bioneer Corporation, Daejeon, Korea, Republic of.
RATIONALE: SiRNA silencing approach has long been used as a method to regulate the expression of specific target gene in vitro and in vivo. However, the effectiveness of delivery and the nonspecific immune stimulatory function of siRNA are the limiting factors for therapeutic application of siRNAs. METHODS: To overcome limitations in in vivo delivery of siRNA, we developed self-assembled micelle inhibitory RNA (SAMiRNA) nanoparticles made of individually bi-conjugated siRNA with hydrophilic polymer and lipid on their ends and characterized their stability, immune stimulatory function and in vivo silencing efficacy. RESULTS: SAMiRNA form very stable nanoparticles with no significant degradation in the size distribution and polydispersity index over 1 year. Overnight incubation of SAMiRNA on murine PBMC did not cause any significant elaboration of innate immune cytokines such as TNF-α, IL-12 or IL-6, while unmodified siRNA or, liposome or liposome complex significantly stimulated the expression of these cytokines. Lastly, in vivo silencing efficacy of SAMiRNA was evaluated by targeting amphiregulin (AR) in bleomycin or TGF-β transgenic (Tg) animal models of pulmonary fibrosis. Only two or three times of intratracheal (i.t.) or intravenous (i.v.) delivery of AR SAMiRNA significantly reduced the bleomycin- or TGF-β-stimulated collagen accumulation in the lung and substantially restored the lung function of TGF- β Tg mice. CONCLUSION : SAMiRNA is a safe, stable and effective platform for silencing disease-associated genes, useful in therapeutic applications for IPF and various fibrotic diseases. Currently we are developing a First-in-class IPF RNAi drugs through Non-clinical toxicology studies.
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