Oligonucleotides targeting frataxin and related methods

An antisense oligonucleotide comprising a 3′ end, a 5′ end, a mixture of modified nucleotides, and a region of complementarity to an intron of a frataxin (FXN) pre-mRNA transcript,

• wherein the mixture of modified nucleotides comprises four consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 3′ end of the antisense oligonucleotide, five consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 5′ end of the antisense oligonucleotide, and at least one 2′-deoxy modified nucleotide,
• wherein the antisense oligonucleotide is between 10 nucleotides to 30 nucleotides in length wherein the region of complementarity is at least 70% complementary to a target segment of SEQ ID NO:
• 6 or SEQ ID NO:
• 10, and
• wherein the antisense oligonucleotide is fully complementary to the target segment of SEQ ID NO:
• 6 or SEQ ID NO:10.

An antisense oligonucleotide comprising:

• a region of complementarity to an intron of a FXN pre-mRNA transcript;
• and
• the formula:
• A-B-C, wherein:
• A comprises about 5 consecutive 2′-O-(2-methoxyethyl) (MOE) modified nucleotides, B comprises about 9 consecutive DNA-like nucleotides, and C comprises about 4 consecutive 2′-O-(2-methoxyethyl) (MOE) modified nucleotides;
• wherein the region of complementarity is at least 70% complementary to a target segment of 10 nucleotides to 30 nucleotides of SEQ ID NO:
• 6 or SEQ ID NO:
• 11.

An antisense oligonucleotide comprising a 3′ end, a 5′ end, a mixture of modified nucleotides, and a region of complementarity to an intron of a frataxin (FXN) pre-mRNA transcript,

• wherein the mixture of modified nucleotides comprises four consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 3′ end of the antisense oligonucleotide, five consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 5′ end of the antisense oligonucleotide, and at least one 2′-deoxy modified nucleotide,
• wherein the antisense oligonucleotide is between 10 nucleotides to 30 nucleotides in length wherein the region of complementarity is at least 70% complementary to a target segment of SEQ ID NO:
• 6 or SEQ ID NO:
• 10, and
• wherein the antisense oligonucleotide comprises a nucleic acid sequence with at least 90% sequence identity to the nucleic acid sequence set forth in any one of SEQ ID NOs:
• 13, 14, or 15 (SEQ ID NO:
• 13-GUACAAACUCCGGAGAGC), (SEQ ID NO:
• 14-GCAAUACATGGATTGGGG), (SEQ ID NO:
• 15-GCAAUACAUGGAUUGGGG).

An antisense oligonucleotide comprising:

• a region of complementarity to an intron of a FXN pre-mRNA transcript;
• and
• a sequence modification pattern of:
• XsXsXsXsXsXsXsXsXsXsXsXsXsXsXsXsXsX, wherein
• s represents a phosphorothioate internucleoside linkage;
• X comprises an adenosine, a guanosine, a cytidine, a thymine, or a uracil, wherein X comprises a 2′-O-(2-methoxyethyl) modification;
• and
• X comprises an adenosine, a guanosine, a cytidine, a thymine, or a uracil, wherein X comprises a 2′-deoxy modification;
• wherein the region of complementarity is at least 70% complementary to a target segment of 10 nucleotides to 18 nucleotides of SEQ ID NO:
• 6 or SEQ ID NO:
• 11.

An antisense oligonucleotide comprising the sequence:

• GsCsAsAsUsAsCsAsTsGsGsAsTsTsGsGsGsG (SEQ ID NO:
• 14), wherein
• s represents a phosphorothioate internucleoside linkage;
• A comprises an adenosine comprising a 2′-O-(2-methoxyethyl) modification;
• G comprises a guanosine comprising a 2′-O-(2-methoxyethyl) modification;
• C comprises a cytidine comprising a 2′-O-(2-methoxyethyl) modification;
• U comprises a thymine comprising a 2′-O-(2-methoxyethyl) modification;
• A comprises an adenosine comprising a 2′-deoxy modification;
• G comprises a guanosine comprising a 2′-deoxy modification;
• C comprises a cytidine comprising a 2′-deoxy modification;
• and
• T comprises a thymine comprising a 2′-deoxy modification.

An antisense oligonucleotide comprising a 3′ end, a 5′ end, a mixture of modified nucleotides, and a region of complementarity to an intron of a frataxin (FXN) pre-mRNA transcript,

• wherein the mixture of modified nucleotides comprises four consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 3′ end of the antisense oligonucleotide, five consecutive 2′-O-methoxyethyl modified ribonucleotides located at the 5′ end of the antisense oligonucleotide, and at least one 2′-deoxy modified nucleotide,
• wherein the antisense oligonucleotide is between 10 nucleotides to 30 nucleotides in length wherein the region of complementarity is at least 70% complementary to a target segment of SEQ ID NO:
• 6 or SEQ ID NO:10, and
• wherein the region of complementarity is at least 70% complementary to a target segment of 10 nucleotides to 20 nucleotides of SEQ ID NO:
• 7 or SEQ ID NO:
• 11.