Compositions comprising therapeutic nucleic acid and saponin for the treatment of muscle-wasting disorders

Composition for use according to any one of the preceding claims, wherein the aldehyde group at position C-23 of the saponin's aglycone core structure is either a free aldehyde group, or is an aldehyde group substituted by a maleimide-comprising moiety attached at said position C-23 with a cleavable covalent bond that cleaves off under acidic conditions present in endosomes and/or lysosomes of human cells, wherein said aldehyde group at position C-23 of the saponin's aglycone core structure is restored upon said cleavage under acidic conditions present in endosomes and/or lysosomes of human cells;

• preferably wherein the cleavable covalent bond is selected from a semicarbazone bond, a hydrazone bond, or a hydrazide bond;
• more preferably being selected from a semicarbazone bond and a hydrazone bond;
• most preferably being a hydrazone bond.

Composition for use according to any one of the preceding claims, wherein the saponin is a free saponin defined as consisting of one or more saponin molecules devoid of a direct or indirect covalent conjugation to a macromolecule such as a nucleic acid or a ligand.

Composition for use according to any one of the preceding claims, wherein the saponin's aglycone core structure is selected from any one or more of quillaic acid, gypsogenin, and a derivative thereof, preferably wherein the saponin's aglycone core structure is quillaic acid or gypsogenin, more preferably quillaic acid.

Composition for use according to any one of the preceding claims, wherein the saponin is at least a bidesmosidic saponin comprising a first saccharide chain that comprises a terminal glucuronic acid residue and comprises a second saccharide chain that comprises at least four sugar residues in a branched configuration;

• preferably wherein the first saccharide chain is Gal-(1→2)-[Xyl-(1→3)]-GlcA and/or wherein the branched second saccharide chain of at least four sugar residues comprises a terminal fucose residue and/or a terminal rhamnose residue.

Composition for use according to any one of the preceding claims, wherein the saponin is any one or more of AG1856, GE1741, a saponin isolated from Quillaja saponaria, Quil-A, QS-17, QS-21, QS-7, SA1641, a saponin isolated from Saponaria officinalis, Saponarioside B, SO1542, SO1584, SO1658, SO1674, SO1700, SO1730, SO1772, SO1832, SO1861, SO1862 and SO1904;

• preferably wherein the saponin is any one or more of QS-21, SO1832, AG1856, SO1861, SA1641 and GE1741;
• more preferably wherein the saponin is QS-21, SO1832 or SO1861;
• most preferably being SO1861.

Composition for use according to any one of the preceding claims, wherein the saponin is a saponin isolated from Saponaria officinalis, preferably wherein the saponin is any one or more of Saponarioside B, SO1542, SO1584, SO1658, SO1674, SO1700, SO1730, SO1772, SO1832, SO1861, SO1862 and SO1904;

• more preferably wherein the saponin is any one or more of SO1832, SO1861 and SO1862;
• even more preferably wherein the saponin is SO1832 and SO1861;
• most preferably being SO1861.

Composition for use according to any one of the preceding claims, wherein the nucleic acid is an oligonucleotide defined as a nucleic acid that is no longer than 150 nt, preferably wherein the oligonucleotide has a size of 5-150 nt, preferably being 8-100 nt, most preferably being 10-50 nt, more preferably wherein the oligonucleotide is an antisense oligonucleotide, even more preferably being a mutation specific antisense oligonucleotide, most preferably being an oligonucleotide designed to induce exon skipping.

Composition for use according to any one of the preceding claims, wherein the nucleic acid is a plasmid or another circular genetic construct.

Composition for use according to any one of the preceding claims, wherein the nucleic acid comprises or consists of any one of the following:

• morpholino phosphorodiamidate oligomer (PMO), 2′-O-methyl (2′-OMe) phosphorothioate RNA, 2′-O-methoxyethyl (2′-O-MOE) RNA {2′-O-methoxyethyl-RNA (MOE)}, locked or bridged nucleic acid (BNA), 2′-0,4′-aminoethylene bridged nucleic acid (BNANC), peptide nucleic acid (PNA), 2′-deoxy-2′-fluoroarabino nucleic acid (FANA), 3′-fluoro hexitol nucleic acid (FHNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), silencing RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), antagomir (miRNA antagonists), aptamer RNA or aptamer DNA, single-stranded RNA or single-stranded DNA, double-stranded RNA (dsRNA) or double-stranded DNA;
• preferably wherein the nucleic acid comprises or consists of a morpholino phosphorodiamidate oligomer (PMO) or a 2′-O-methyl (2′-OMe) phosphorothioate RNA.

Composition for use according to any one of the preceding claims, wherein the nucleic acid is designed to induce exon skipping of the human dystrophin gene transcript, preferably wherein the exon skipping involves exon 51 skipping or exon 53 skipping or exon 45 skipping;

• more preferably wherein the nucleic acid is a 2′O-methyl-phosporothioate antisense oligonucleotide or a phosphorodiamidate morpholino oligomer antisense oligonucleotide that is designed to induce the exon 51 skipping or the exon 53 skipping or the exon 45 skipping,
• even more preferably wherein the nucleic acid is selected from eteplirsen, drisapersen, golodirsen, viltolarsen, and casimersen.

Composition for use according to any one of the preceding claims, wherein the composition comprises two or more different nucleic acids, preferably being two or more different oligonucleotides, more preferably wherein at least one of the two or more different oligonucleotides is an antisense oligonucleotide.

Composition for use according to any one of the preceding claims, wherein the nucleic acid is conjugated with a ligand of an endocytic receptor on a muscle cell.

Composition for use according to any one of the preceding claims, wherein the saponin is or comprises at least one molecule of any of SO1861, SO1861-EMCH, or SO1861-SC-Maleimide, preferably SO1861-EMCH or SO1861-SC-Maleimide, the nucleic acid is drisapersen or eteplirsen, and the ligand conjugated with the nucleic acid is antiCD71 antibody or a binding fragment thereof.

Composition for use according to any one of the preceding claims, for use in intravenous or subcutaneous administration to a human subject.

Composition for use according to any one of the preceding claims, the composition comprising a pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

Composition for use according to any one of the preceding claims, the composition comprising 2-6 μM of the saponin, preferably being 3-5 μM, more preferably being 3.5-4.5 μM, and most being about 4 μM.