In our previous work, bicyclic oxazaphospholidine (OAP) monomers were used to prepare a series of phosphorothioate (PS)-modified gapmer antisense oligonucleotides (ASOs).  In these we controlled the chirality of each of the PS linkages within the 10-base gap and leaft the wing regions stereo-random.  Compounds that had 9 or more Sp- linkages in the gap were found to be poorly active <i>in vitro</i> for the reduction of scavenger receptor SR-B1 mRNA in primary hepatocytes. Compounds with uniform Rp-gaps exhibited activity very similar to that of the stereo-random parent ASOs in cell culture.  Conversely, when tested <i>in vivo</i>, the full Rp-gap compound was found to be rapidly metabolized, resulting in low activity.  In this study, a series of ASOs targeting Malat-1 or Lrrk2 mRNA were prepared using OAP chemistry to control PS chirality in both the wing and gap regions.  The effects of controlling PS chirality on ASO potency, toxicity, distribution, and duration of action in the CNS will be presented.

Controlling chirality of phosphorothioate linkages in the DNA gap does not enhance potency of gapmer antisense oligonucleotides (ASO) in the liver or CNS

2019 Spring National Meeting

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