US 12,441,999 B2
Hybrid htiRNA/nanoparticle complex and use thereof for treating a disease of the digestive system
Fabrice Navarro Y Garcia, Grenoble (FR); Dorothee Jary, Grenoble (FR); and Adrien Nougarede, Grenoble (FR)
Assigned to COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES, Paris (FR)
Appl. No. 17/627,040
Filed by COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES, Paris (FR)
PCT Filed Jul. 15, 2020, PCT No. PCT/EP2020/070022
§ 371(c)(1), (2) Date Jan. 13, 2022,
PCT Pub. No. WO2021/009242, PCT Pub. Date Jan. 21, 2021.
Claims priority of application No. 19 07965 (FR), filed on Jul. 15, 2019.
Prior Publication US 2023/0136944 A1, May 4, 2023
Int. Cl. C12N 15/113 (2010.01); A61K 9/1271 (2025.01)
CPC C12N 15/113 (2013.01) [A61K 9/1271 (2013.01)] 14 Claims
 
1. A hybrid DNA/RNA molecule, called htiRNA hybrid, comprising:
two antisense RNA strands of same sequences and able to modulate endogenous mechanisms of RNA interference, each comprising a number of nucleotides nRNA in a range of from 18 to 30, and having a phosphorylated 5′ end;
a first DNA strand, having a nucleotide sequence comprising a nucleotide sequence S1 linked via its 3′ end to the 5′ end of a nucleotide spacer arm L1 linked by its 3′ end to the 5′ end of a nucleotide sequence SC1; and
a second DNA strand, having a nucleotide sequence comprising a nucleotide sequence S2 linked via its 3′ end to the 5′ end of a nucleotide spacer arm L2 inked via its 3′ end to the 5′ end of a nucleotide sequence SC2,
wherein the nucleotide sequence SC1 comprises a number nsc1 of nucleotides with nsc1 from (nRNA−3) to (NRNA+3), and has at least 40% sequence identity, determined by a global alignment method, with the complementary sequence of the antisense RNA, so that the nucleotide sequence SC1 is hybridized via complementarity to a first of the two antisense RNA strands,
wherein the nucleotide sequence SC2 comprises a number nsc2 of nucleotides with nsc2 from (nRNA−3) to (nRNA+3), and has at least 40% sequence identity, determined by a global alignment method, with the complementary sequence of the antisense RNA, so that the nucleotide sequence SC2 is hybridized via complementarity to the second of the two antisense RNA strands,
wherein the nucleotide sequence S1 of the first DNA strand is complementary to the nucleotide sequence S2 of the second DNA strand, so that the nucleotide sequence S1 of the first DNA strand is hybridized via complementarity to the nucleotide sequence S2 of the second DNA strand,
wherein the two nucleotide sequences S1 and S2 have the same number ns1-s2 of nucleotides, ns1-s2 being a number in a range of from 16 to 30,
wherein the nucleotide spacer arm L1 of the first DNA strand comprises a number nL2 of nucleotides and the nucleotide spacer arm L2 of the second DNA strand comprises a number nL2 of nucleotides, nL1 and nL2 independently being a number in a range of from 1 to 15, and
wherein the two antisense RNA strands, the first DNA strand, and/or the second DNA strand optionally carry one or more lipid groups.