Hydrophobically modified antisense oligonucleotides comprising a cetal group or a triple alkyl chain to improve intracellular delivery and efficacy of antisense oligonucleiotide

The present invention concerns an oligonucleotide modified by substitution at the 3’ or the 5’ end by at least triple alkyl chain or at least one ketal functional group, wherein the ketal carbon bears two hydrocarbon chains. The invention also concerns the use of the hydrophobically modified oligonucleotides as a medicament, in particular for use for treating cancer. The autors show lipid conjugate Antisense Oligonucleotide (L-ASO) are capable of inhibiting prostate cancer in vivo and have no toxicity in mice (Karaki S et al. 2017 J Control Release, 258:1-9). The addition of a lipid chain on the 5’ part of the antisense oligonucleotide enables inhibiting specifically “UD protein”, even in the absence of the transfection agent. The lipid modification strongly enhances the ability of ASO to reduce “UD protein” expression leading to a strong reduction of tumor progression in a murin xenograft model of Castration Resistant prostate cancer. The L-ASO have been validated in others therapeutic indications. These modifications allow advantages over standard ASO: 1/ Delivery enhancement, Stability, biodisponibility; 2/ Internalisation without any transfection agents; 3/ Encapsulation of different molecules like chemotherapies (L-ASOs self-assembly give sphericals nanoparticles, which are prone to host drug molecules within their hydrophobic cores: for instance Paclitaxel).

Keywords: Nucleic acids, Antisense, Oligonuceotides, Encapsulation, Nanoparticles.
Patent Application number: PCT/IB2013/001516
Inventors:
Philippe BARTHELEMY Julie ACUNZO Khalid OUMZIL Arnaud GISSOT Palma ROCCHI
Publications:
J Control Release. 2017 Jul 28;258:1-9. doi: 10.1016/j.jconrel.2017.04.042. Epub 2017 May 1. Bioconjug Chem. 2013 Aug 21;24(8):1345-55. Chem Soc Rev. 2011 Dec;40(12):5844-54. doi: 10.1039/c1cs15038c. Epub 2011 May 24.

Reference:

CHIM13035-T1

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Patent filling date: 2013-06-05

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