Treatment of nuclear respiratory factor 1 (NRF1) related diseases by inhibition of natural antisense transcript to NRF1
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Nuclear Respiratory Factor 1 (NRF1), in particular, by targeting natural antisense polynucleotides of Nuclear Respiratory Factor 1 (NRF1). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of NRF1.
1. A method of upregulating a function of and/or the expression of a Nuclear Respiratory Factor 1 (NRF 1) polynucleotide having SEQ ID NO: 1 in patient cells or tissues in vivo or in vitro comprising:
contacting said cells or tissues with at least one antisense oligonucleotide 12 to 30 nucleotides in length wherein said at least one oligonucleotide is specific for a natural antisense polynucleotide of the NRF1 polynucleotide and is selected from a single stranded oligonucleotide or a double stranded siRNA oligonucleotide wherein a single strand thereof has at least 80% sequence identity to a reverse complement of said natural antisense polynucleotide of a Nuclear Respiratory Factor 1(NRF1) polynucleotide; thereby upregulating a function of and/or the expression of the Nuclear Respiratory Factor 1 (NRF1) polynucleotide in patient cells or tissues in vivo or in vitro.
2. A method of upregulating a function of and/or the expression of a Nuclear Respiratory Factor 1 (NRF1) polynucleotide having SEQ ID NO: 1 in patient cells or tissues in vivo or in vitro comprising:
contacting said cells or tissues with at least one antisense oligonucleotide 19 to 30 nucleotides in length wherein said ohgonucicotidc is specific for a natural antisense polynucleotide of the NRF1 polynucleotide and is selected from a single stranded oligonucleotide or a double stranded siRNA oligonucleotide wherein a single strand thereof has at least 90% sequence identity to a 19 to 30 nucleotide region of an RNA transcribed from the Nuclear Respiratory Factor 1 (NRF1) polynucleotide; thereby upregulating function of and/or the expression of the Nuclear Respiratory Factor 1 (NRF1) polynucleotide in patient cells or tissues in vivo or to vitro.
3. A method of upregulating a function of and/or the expression of a Nuclear Respiratory Factor 1 (NRF1) polynucleotide having SEQ ID NO: 1 in patient cells or tissues in vivo or in vitro comprising:
contacting said cells or tissues with at least one single stranded antisense oligonucleotide or double stranded siRNA oligonucleotide of 10 to 30 nucleotides in length that specifically targets a 10 to 30 nucleotide region of a natural antisense oligonucleotide of the Nuclear Respiratory Factor 1 (NRF1) polynucleotide; thereby upregulating a function of and/or the expression of the Nuclear Respiratory Factor 1 (NRF1) polynucleotide in patient cells or tissues vivo or in vitro.
4. The method of claim 3 , wherein a function of and/or the expression of the Nuclear Respiratory Factor 1 (NRF1) is increased in vivo or in vitro with respect to a control.
5. The method of claim 3 , wherein the at least one antisense oligonucleotide targets a natural antisense sequence of as Nuclear Respiratory Factor 1 (NRF1) polynucleotide haying SEQ ID NO: 2.
6. The method of claim 3 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide antisense to coding and/or coding and non-coding nucleic acid sequences of a Nuclear Respiratory Factor 1 (NRF 1) polynucleotide.
7. The method of claim 3 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide having overlapping and/or non-overlapping sequences with a Nuclear Respiratory Factor 1 (NRF1) polynucleotide.
8. The method of claim 3 , wherein the at least one antisense oligonucleotide comprises one or more modifications selected from: at least one modified sugar moiety, at least one modified intemucicoside linkage, at least one modified nucleotide, and combinations thereof.
9. The method of claim 8 , 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′-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and combinations thereof.
10. The method of claim 8 , wherein the one or more modifications comprise at least one modified imernucleoside linkage selected from: a phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof.
11. The method of claim 8 , 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-nueleic acid (FANA), an analogue, a derivative, and combinations thereof.
12. The method of claim 3 , wherein the at least one oligonucleotidc comprises at least one oligonucleotide sequences set forth as SEQ ID NOS: 3 to 5.
13. A method of upregulating a function of and/or the expression of Nuclear Respiratory Factor 1 (NRF1) polynucleotide having SEQ ID NO: 1 in mammalian cells or tissues in vivo or in vitro comprising:
contacting said cells or tissues with at least one single stranded antisense olinonueleotide or double stranded siRNA oligonucleotide of about 12 to 30 nucleotides in length specific for noncoding and/or coding sequences of a natural antisense strand of a Nuclear Respiratory Factor 1 (NRF1) pohmueleotide wherein said at least one antisense oligonucleotide has at least 80% sequence identity to at least one nucleic acid sequence set forth as SEQ ID NOS: 1 or an RNA polynucleotide transcribed from the NRF1 polynucleotide; and, upregulating the function and/or expression of the Nuclear Respiratory Factor 1 (NRF1) in mammalian cells or tissues in vivo or in vitro.