PHYTOECDYSONES AND/OR 20-HYDROXYECDYSONE DERIVATIVES IN COMBINATION WITH AN ACTIVE INGREDIENT FOR RESTORING SMN EXPRESSION, FOR USE IN THE TREATMENT OF SPINAL MUSCULAR ATROPHY
The invention relates to at least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein, for use in a combination therapy In the treatment of spinal muscular atrophy in mammals.
1 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein, for use in the treatment of spinal muscular atrophy in mammals.
2 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to claim 1 , for use in the treatment of a motor neuron disease responsible for spinal muscular atrophy.
3 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to claim 2 , wherein the motor neuron disease is an alteration in the function of the motor neurons or the degeneration thereof.
4 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 1 to 3 , wherein the active ingredient has the ability to increase the production of functional SMN protein by gene therapy or by therapy of the gene.
5 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 1 to 3 , wherein the active ingredient has the ability to increase the production of functional SMN protein by providing the SMN1 gene or by acting on the maturation of the SMN2 gene.
6 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 1 to 3 , wherein the active ingredient has the ability to increase the production of functional SMN protein is an antisense oligonucleotide.
7 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to claim 6 , wherein the antisense oligonucleotide includes 10 to 30 nucleotides.
8 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 7 , wherein the antisense oligonucleotide is complementary to at least 90%, preferably at least 95%, most preferably at least 98%, preferably 100%, of the sequence of the nucleic acid encoding the pre-mRNA of the human SMN2 gene.
9 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 8 , wherein the antisense oligonucleotide is complementary to at least 90%, preferably at least 95%, most preferably 98%, preferably 100%, of a sequence belonging to intron 6, intron 7 or exon 7 of the nucleic acid encoding the pre-mRNA of the human SMN2 gene.
10 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 9 , wherein the antisense oligonucleotide is a sequence which is identical or similar to at least 50% with the sequence SEQ ID NO: 1, preferably identical or similar to at least 60%, preferably to at least 70%, more preferably to at least 80%, most preferably to at least 90% and preferably identical or similar to 100%.
11 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 9 , wherein the ASO has a sequence selected from the sequences SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29.
12 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 11 , wherein the ASO includes at least one modification selected from:
a modification at the phosphate group such as a phosphorothioate, or a methylphosphanate, or a phosphoroamidate,
a chemical modification in the 2′ position of the ribose, such as a 2′O-methyl (2′OMe) or a 2′O-methoxyethyl (2′MOE) or a 2′ Fluoro (2′ F),
at least one modification of nucleobases such as the methylation of 5′ methylcytosine, 5-methyluridine/ribothymidine, or “G-clamp” type pyrimidine,
at least one substantial change in the sugar structure, leading to a variety of molecules, such as morpholinos or the peptide nucleic acids or oligonucleotides of constrained type.
13 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 6 to 9 , wherein the antisense oligonucleotide is a sequence which is identical or similar to at least 50% with the sequence SEQ ID NO: 23, preferably identical or similar to at least 60%, preferably at least 70%, more preferably at least 80%, most preferably at least 90% and preference identical or similar to 100%.
14 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 1 to 13 , wherein said at least one phytoecdysone is 20-hydroxyecdysone.
15 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to claim 14 , wherein 20-hydroxyecdysone is in the form of a plant extract or a plant portion, said extract including at least 95%, and preferably at least 97%, of 20-hydroxyecdysone.
16 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 1 to 15 , wherein said at least one semi-synthetic derivative of 20-hydroxyecdysone is selected from:
a compound of general formula (I):
wherein:
R 1 is selected from: a (C 1 -C 6 ) W(C 1 -C 6 ) group; a (C 1 -C 6 ) W(C 1 -C 6 ) W(C 1 -C 6 ) group; a (C 1 -C 6 ) W(C 1 -C 6 ) CO 2 (C 1 -C 6 ) group; a (C 1 -C 6 ) A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, (C 1 -C 6 ), N(C 1 -C 6 ), CO 2 (C 1 -C 6 ) type; a CH 2 Br group;
W being a heteroatom selected from N, O and S, preferably O and even more preferably S°; and,
a compound having formula (II):
17 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to claim 16 , wherein in general formula (I):
R 1 is selected from: a (C 1 -C 6 ) W(C 1 -C 6 ) group; a (C 1 -C 6 ) W(C 1 -C 6 ) W(C 1 -C 6 ) group; a (C 1 -C 6 ) W(C 1 -C 6 ) CO 2 (C 1 -C 6 ) group; a (C 1 -C 6 ) A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, (C 1 -C 6 ), N(C 1 -C 6 ), CO 2 (C 1 -C 6 ) type;
W being a heteroatom selected from N, O and S, preferably O and more preferably S.
18 . At least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the ability to increase the production of functional SMN protein for the use thereof according to any one of claims 16 to 17 , wherein at least one compound of general formula (I) is selected from:
no. 1: (2S,3R,5R,10R,13R,14S, 17S)-2,3,14-trihydroxy-10,13-dimethyl-17-(2-morpholinoacetyl)-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one,
no. 2: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(3-hydroxypyrrolidin-1-yl) acetyl]-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one;
no. 3: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(4-hydroxy-1-piperidyl) acetyl]-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one;
no. 4: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-[4-(2-hydroxyethyl)-1-piperidyl]acetyl]-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one;
no. 5: (2S,3R,5R,10R,13R,14S, 17S)-17-[2-(3-dimethylaminopropyl (methyl)amino) acetyl]-2,3,14-trihydroxy-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one;
no. 6:2-[2-oxo-2-[(2S,3R,5R,10R, 13R,14S,17S)-2,3,14-trihydroxy-10,13-dimethyl-6-oxo-2,3,4,5,9,11,12,15,16,17-décahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl]ethylsulfanylacetate;
no. 7: (2S,3R,5R,10R,13R,14S, 17S)-17-(2-ethylsulfanylacetyl)-2,3,14-trihydroxy-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-6-one;
no. 8: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(2-hydroxyethyl sulfanyl) acetyl]-10,13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H cyclopenta[a]phenanthren-6-one.
19 . Composition comprising:
at least one phytoecdysone and/or at least one semi-synthetic derivative of 20-hydroxyecdysone,
at least one active ingredient having the ability to increase the production of functional SMN protein,
for the use thereof in the treatment of spinal muscular atrophy in mammals.