Double-stranded oligonucleotide compound for down-regulating the expression of CASP2 gene
View Patent ↗The present invention relates to compositions and methods for inhibiting loss of a retinal ganglion cell in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at 5 least one siRNA which down regulates expression of a target gene associated with loss of the retinal ganglion cell, thereby inhibiting loss of the retinal ganglion cell in the subject. The methods of the invention also relate to the use of chemically modified siRNA compounds possessing structural motifs which down-regulate the expression of human genes expressed in retinal tissue in the mammalian eye.
1. A double-stranded oligonucleotide having the structure:
5′ iB-GCCAGAAUGUGGAACUCCU 3′ (sense strand; SEQ ID
NO: 9015)
3′ CGGUCUUACACCUUGAGGA 5′ (antisense strand;
SEQ ID NO: 9516)
wherein each of A, C, U, and G is a nucleotide and each consecutive nucleotide is joined to the next nucleotide by a phosphodiester bond;
wherein the sense strand comprises, counting from the 5′ terminus, an unmodified ribonucleotide at each of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 19, a L-deoxycytidine at position 18, and an inverted deoxyabasic moiety (iB) covalently attached at the 5′terminus; and
wherein the antisense strand comprises, counting from the 5′ terminus, a 2′-O-Methyl sugar-modified ribonucleotide at each of positions 2, 4, 6, 8, 11, 13, 15, 17 and 19 and an unmodified ribonucleotide at each of positions 1, 3, 5, 7, 9, 10, 12, 14, 16 and 18; or
a pharmaceutically acceptable salt of the double-stranded oligonucleotide.
2. A composition comprising the double-stranded oligonucleotide or a pharmaceutically acceptable salt of the double-stranded oligonucleotide according to claim 1 ; and a pharmaceutically acceptable carrier.
3. The double-stranded oligonucleotide according to claim 1 .
4. A pharmaceutically acceptable salt of the double-stranded oligonucleotide according to claim 1 .
5. The composition according to claim 2 comprising the double-stranded oligonucleotide.
6. The composition of claim 2 comprising a pharmaceutically acceptable salt of the double-stranded oligonucleotide.
7. A composition comprising the double-stranded oligonucleotide or a pharmaceutically acceptable salt of double-stranded oligonucleotide according to claim 1 , in an amount effective to down-regulate expression of a CASP2 gene; and a pharmaceutically acceptable carrier.
8. The composition of claim 7 comprising the double-stranded oligonucleotide.
9. The composition of claim 7 comprising a pharmaceutically acceptable salt of the double-stranded oligonucleotide.