Unlocking the full potential of oligonucleotide therapeutics to address unmet medical needs requires development of strategies for efficient and functional delivery of oligonucleotides to target cells outside of the liver. We established a collaboration to explore extrahepatic delivery of chemically stabilized siRNAs as direct conjugates with Centyrins, a novel class of highly stable FN3 domain alternative scaffold proteins. This presentation will discuss preparation, characterization, in vitro and in vivo gene silencing properties of Centyrin – siRNA conjugates. Centyrins have been selected for conjugation on the basis of highly efficient internalization in target cells through receptor mediated endocytosis. Chemical and chemoenzymatic coupling of siRNA to Centyrins has yielded stable, well-behaved, fully homogeneous conjugates with good plasma stability. In vitro, these conjugates have demonstrated ability to knock down expression of mRNA and protein in cells expressing receptor target of the corresponding Centyrin, in the absence of transfection reagent. In vivo, Centyrin-siRNA conjugates induced robust gene silencing in mouse tumor xenograft model with RNAi mechanism confirmation obtained through 5’ RACE assay on tumor samples.

Designed FN3 domains for extrahepatic delivery of oligonucleotides

2019 Fall National Meeting

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