NEW CONJUGATED NUCLEIC ACID MOLECULES AND THEIR USES

1 - 25 . (canceled)

26 . A conjugated nucleic acid molecule comprising a double-stranded nucleic acid moiety, the 5′ end of the first strand and the 3′ end of the complementary strand being linked together by a loop, and optionally a molecule facilitating the endocytosis which is linked to the loop,

wherein

the length of the double-stranded nucleic acid moiety is from 10 to 20 base pairs;

the sequence of the double-stranded nucleic acid moiety has less than 80% sequence identity to any gene in a human genome;

the double-stranded nucleic acid moiety comprises deoxyribonucleotides and up to 30% of ribonucleotides or modified deoxyribonucleotides with respect to the total number of nucleotides of the nucleic acid molecule; and

the loop has a structure selected from one of the following formulae:

—O—P(X)OH—O—{[(CH 2 ) 2 —O] g —P(X)OH—O} r —K—O—P(X)OH—O—{[(CH 2 ) 2 —O] h —P(X)OH—O—} s   (I)

with r and s being independently an integer 0 or 1; g and h being independently an integer from 1 to 7 and the sum g+h being from 4 to 7;

with K being

with i, j, k and 1 being independently an integer from 0 to 6;

or

—O—P(X)OH—O—[(CH 2 ) d —C(O)—NH] b —CHR—[C(O)—NH—(CH 2 ) e ] c —O—P(X)OH—O—  (II)

with b and c being independently an integer from 0 to 4, and the sum b+c is from 3 to 7;

d and e being independently an integer from 1 to 3; and

with R being -L f -J,

X being O or S, L being a linker and f being an integer being 0 or 1, and J being a molecule facilitating the endocytosis or being H.

27 . The conjugated nucleic acid molecule according to claim 26 , wherein the nucleic acid molecule comprises one of the following sequences:

(SEQ ID NO 1)

5′CCCAGCAAACAAGCCT-∫

3′GGGTCGTTTGTTCGGA-∫

and

(SEQ ID NO 2)

5′CAGCAACAAG-∫

3′GTCGTTGTTC-∫

or a sequence wherein 1 to 3 nucleotides are substituted by a ribonucleotide or a modified deoxyribonucleotide or ribonucleotide.

28 . The conjugated nucleic acid molecule according to claim 26 , wherein the molecule facilitating the endocytosis is selected from the group consisting of a cholesterol, single or double chain fatty acids, ligand which targets a cell receptor enabling receptor mediated endocytosis, or a transferrin.

29 . The conjugated nucleic acid molecule according to claim 26 , wherein the molecule facilitating the endocytosis is a cholesterol.

30 . The conjugated nucleic acid molecule according to claim 26 , wherein the molecule facilitating the endocytosis is a ligand of a sigma-2 receptor (σ2R).

31 . The conjugated nucleic acid molecule according to claim 30 , wherein the ligand of a sigma-2 receptor (σ2R) comprises the following formula:

with n being an integer from 1 to 20.

32 . The conjugated nucleic acid molecule according to claim 26 , wherein 1, 2 or 3 internucleotidic linkages of the nucleotides located at the free end of the double-stranded moiety of the nucleic acid molecule have a modified phosphodiester backbone, optionally on both strands.

33 . The conjugated nucleic acid molecule according to claim 26 , wherein the loop has the formula (I) and K is

34 . The conjugated nucleic acid molecule according to claim 26 , wherein f is 1 and L is —C(O)—(CH 2 ) m —NH—[(CH 2 ) 2 —O] n —(CH 2 ) p —C(O)-J or —C(O)—(CH 2 ) m —NH—[C(O)—CH 2 —O] t —[(CH 2 ) 2 —O] n —(CH 2 ) p —[C(O)] v -J with m being an integer from 0 to 10; n being an integer from 0 to 6; and p being an integer from 0 to 2; t and v being an integer 0 or 1 with at least one among t and v being 1.

35 . The conjugated nucleic acid molecule according to claim 26 , wherein f is 1 and L-J is selected in the group consisting of —C(O)—(CH 2 ) m —NH—[(CH 2 ) 2 —O] n —(CH 2 ) p —C(O)-J, —C(O)—(CH 2 ) m —NH—C(O)—[(CH 2 ) 2 —O] n —(CH 2 ) p -J, —C(O)—(CH 2 ) m —NH—C(O)—CH 2 —O—[(CH 2 ) 2 —O] n —(CH 2 ) p -J, —C(O)—(CH 2 ) m —NH—C(O)—[(CH 2 ) 2 —O] n —(CH 2 ) p —C(O)-J and —C(O)—(CH 2 ) m —NH—C(O)—CH 2 —O—[(CH 2 ) 2 —O] n —(CH 2 ) p —C(O)-J, with m being an integer from 0 to 10; n being an integer from 0 to 15; and p being an integer from 0 to 3.

36 . The conjugated nucleic acid molecule according to claim 26 , wherein the loop has the formula (I)

—O—P(X)OH—O—{[(CH 2 ) 2 —O] g —P(X)OH—O} r —K—O—P(X)OH—O—{[(CH 2 ) 2 —O] h —P(X)OH—O—} s   (I)

with X being S, r being 1, g being 6, s being 0, and K being

with f being 1 and L being C(O)—(CH 2 ) 5 —NH—[(CH 2 ) 2 —O] 3 —(CH 2 ) 2 —C(O)-J, —C(O)—(CH 2 ) 5 —NH—C(O)—[(CH 2 ) 2 —O] 3 —(CH 2 ) 3 -J, —C(O)—(CH 2 ) 5 —NH—C(O)—CH 2 —O—[(CH 2 ) 2 —O] 5 —CH 2 —C(O)-J, —C(O)—(CH 2 ) 5 —NH—C(O)—CH 2 —O—[(CH 2 ) 2 —O] 9 —CH 2 —C(O)-J, —C(O)—(CH 2 ) 5 —NH—C(O)—CH 2 —O— [(CH 2 ) 2 —O] 13 —CH 2 —C(O)-J, or —C(O)—(CH 2 ) 5 —NH—C(O)-J.

37 . The conjugated nucleic acid molecule according to claim 26 , wherein the conjugated nucleic acid molecule is selected from the group consisting of

wherein internucleotide linkages “s” refers to phosphorothioate internucleotide linkages; italic U being 2′-deoxy-2′-fluoroarabinouridine, italic G being 2′-deoxy-2′-fluoroarabinoguanosine; italic C being 2′-deoxy-2′-fluoroarabinocytidine; and the pharmaceutically acceptable salts thereof.

38 . The conjugated nucleic acid molecule according to claim 37 , wherein the conjugated nucleic acid molecule is selected from the group consisting of

wherein internucleotide linkages “s” refers to phosphorothioate internucleotide linkages; italic U being 2′-deoxy-2′-fluoroarabinouridine, italic G being 2′-deoxy-2′-fluoroarabinoguanosine; italic C being 2′-deoxy-2′-fluoroarabinocytidine; or the pharmaceutically acceptable salts thereof.

39 . The conjugated nucleic acid molecule according to claim 26 , wherein the conjugated nucleic acid molecule is

wherein internucleotide linkages “s” refers to phosphorothioate internucleotide linkages; or the pharmaceutically acceptable salts thereof.

40 . A pharmaceutical composition comprising a conjugated nucleic acid molecule according to claim 26 .

41 . The pharmaceutical composition according to claim 40 , wherein the pharmaceutical composition further comprises an additional therapeutic agent selected from an immunomodulator, an immune checkpoint inhibitor (ICI), a T-cell-based cancer immunotherapy, adoptive cell transfer (ACT), genetically modified T-cells or engineered T-cells, chimeric antigen receptor cells (CAR-T cells), a conventional chemotherapeutic, radiotherapeutic or anti-angiogenic agent, HDAC inhibitor, or targeted immunotoxin.

42 . A method of treating a cancer in a subject in need thereof, comprising administering a therapeutically efficient amount of a conjugated nucleic acid molecule according to claim 26 or a pharmaceutical composition comprising said molecule repeatedly or chronically.

43 . The method of treating a cancer according to claim 42 , comprising administering repeated cycles of treatment.

44 . The method of treating a cancer according to claim 42 , wherein the patients have tumors carrying deficiencies in the NAD + synthesis.

45 . The method of treating a cancer according to claim 44 , wherein the tumor cells further carry DNA repair pathways deficiencies selected from ERCC1 or ATM deficiency or IDHs mutations.

46 . A pharmaceutical composition comprising a conjugated nucleic acid molecule according to claim 38 .

47 . A pharmaceutical composition comprising a conjugated nucleic acid molecule according to claim 39 .

48 . A method of treating a cancer in a subject in need thereof, comprising administering a therapeutically efficient amount of a conjugated nucleic acid molecule according to claim 38 or a pharmaceutical composition comprising said molecule repeatedly or chronically.

49 . A method of treating a cancer in a subject in need thereof, comprising administering a therapeutically efficient amount of a conjugated nucleic acid molecule according to claim 39 or a pharmaceutical composition comprising said molecule repeatedly or chronically.