Treatment of sodium channel, voltage-gated, alpha subunit (SCNA) related diseases by inhibition of natural antisense transcript to SCNA
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Sodium channel, voltage-gated, alpha subunit (SCNA), in particular, by targeting natural antisense polynucleotides of Sodium channel, voltage-gated, alpha subunit (SCNA). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of SCNA.
1. A method of upregulating a function of and/or the expression of a Sodium channel, voltage-gated, alpha subunit SCN1A polynucleotide in a biological system having SEQ ID NO: 1 comprising: contacting said biological system with at least one single stranded antisense oligonucleotide 13 to 28 nucleotides in length which targets a 13 to 28 nucleotide region of a long non-coding natural antisense polynucleotide selected from the group consisting of SEQ ID NOS: 12-28 wherein said at least one single stranded oligonucleotide has 100% sequence identity to a reverse complement of a polynucleotide comprising 13 to 28 consecutive nucleotides within the natural antisense polynucleotide of SEQ ID NO: 12 or of SEQ ID NO: 13, or of SEQ ID NO: 14, or of SEQ ID NO:15, or of SEQ ID NO: 16, or of SEQ ID NO: 17, or of SEQ ID NO: 18, or of SEQ ID NO: 19, or of SEQ ID NO: 20, or of SEQ ID NO: 21, or of SEQ ID NO: 22, or of SEQ ID NO: 23, or of SEQ ID NO: 24, or of SEQ ID NO: 25, or of SEQ ID NO: 26, or of SEQ ID NO: 27 or of SEQ ID NO: 28; thereby upregulating a function of and/or the expression of the Sodium channel, voltage-gated, type I, alpha subunit (SCN1A) polynucleotide wherein the at least one oligonucleotide comprises at least one oligonucleotide sequence set forth as SEQ ID NOs: 40-92.
2. A method of upregulating a function of and/or the expression of a human Sodium channel, voltage-gated, alpha subunit (SCN1A) polynucleotide having SEQ ID NO: 1 in a biological system comprising: contacting said system with at least one single stranded antisense oligonucleotide of 13 to 30 nucleotides in length that is 100% complementary to and specifically targets a complementary region of a natural antisense polynucleotide of the Sodium channel, voltage-gated, alpha subunit (SCN1A) polynucleotide wherein said natural antisense polynucleotide is selected from the group consisting of nucleotides 1 to 1123 of SEQ ID NO: 12 and 1 to 2352 of SEQ ID NO: 13, 1 to 267 of SEQ ID NO: 14, 1 to 1080 of SEQ ID NO: 15, 1 to 173 of SEQ ID NO: 16, 1 to 618 of SEQ ID NO: 17, 1 to 871 of SEQ ID NO: 18, 1 to 304 of SEQ ID NO:19, 1 to 293 of SEQ ID NO: 20, 1 to 892 of SEQ ID NO: 21, 1 to 260 of SEQ ID NO: 22, 1 to 982 of SEQ ID NO: 23, 1 to 906 of SEQ ID NO: 24; thereby upregulating a function of and/or the expression of the Sodium channel, voltage-gated, alpha subunit (SCN1A) polynucleotide wherein the at least one oligonucleotide comprises at least one oligonucleotide sequences set forth as SEQ ID NOS: 31, 33, 37, 40 to 92.
3. The method of claim 2 , wherein a function of and/or the expression of the Sodium channel, voltage-gated, alpha subunit (SCN1A) is increased in vivo or in vitro with respect to a control by at least 10%.
4. The method of claim 2 , wherein the at least one antisense oligonucleotide targets a natural antisense sequence of a Sodium channel, voltage-gated, type I, alpha subunit (SCNIA) polynucleotide wherein the natural antisense sequence comprises SEQ ID NO: 12.
5. The method of claim 2 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide antisense to coding sequences of an RNA polynucleotide transcribed from the Sodium channel, voltage-gated, type I, alpha subunit (SCNIA) polynucleotide.
6. The method of claim 2 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide having overlapping and/or non-overlapping sequences with an mRNA polynucleotide of a Sodium channel, voltage-gated, type I, alpha subunit (SCNIA) polynucleotide.
7. The method of claim 2 , wherein the at least one antisense oligonucleotide comprises one or more modifications selected from: at least one modified sugar moiety, at least one modified internucleoside linkage, at least one modified nucleotide, and combinations thereof.
8. The method of claim 7 , wherein the one or more modifications comprise at least one modified sugar moiety selected from: a 2-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-0-alkyl modified sugar moiety, a bicyclic sugar moiety, and combinations thereof.
9. The method of claim 7 , wherein the one or more modifications comprise at least one modified internucleoside linkage selected from: a phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof.
10. The method of claim 7 , wherein the one or more modifications comprise at least one modified nucleotide selected from: a peptide nucleic acid (PNA), a locked nucleic acid (LNA), an arabino-nucleic acid and combinations thereof.
11. The method of claim 2 , wherein the at least one oligonucleotide comprises at least one oligonucleotide sequence set forth as SEQ ID NOs: 50-92.
12. The method according to claim 2 wherein the oligonucleotide is selected from SEQ ID NO: 70.