Antisense-induced exon2 inclusion in acid alpha-glucosidase

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• each Nu is a nucleobase which taken together forms a targeting sequence;
• x is an integer from 18 to 38;
• each Y is independently selected from O or —NRa, wherein Ra is selected from the group consisting of hydrogen, -T1-NRcRdRe, and a cell penetrating peptide, wherein:
• Rc is selected from the group consisting of hydrogen, C1-C6 alkyl, aralkyl, and —C(═NH)NH2,
• Rd is selected from the group consisting of hydrogen, aralkyl, and C1-C6 alkyl, or
• Rc and Rd taken together with the nitrogen atom to which they are attached form a 5-7 membered ring when Rc and Rd are each independently C1-C6 alkyl or aralkyl, where the ring is optionally substituted with a substituent selected from the group consisting of C1-C6 alkyl, phenyl, halogen, and aralkyl, and
• Re is selected from the group consisting of an electron pair, hydrogen, C1-C6 alkyl, and aralkyl;
• each L is independently selected from the group consisting of:
• and a cell penetrating peptide, wherein w is an integer selected from 3-20, and S is an integer selected from 1 to 8;
• n is an integer from 0 to 3;
• each R1 is independently selected from the group consisting of —N(CH3)2, —NR5R6, —OR7, a moiety of formula (II):
• wherein:
• R8 is selected from the group consisting of hydrogen, methyl, —C(═NH)NH2, —Z-T2-NHC(═NH)NH2, and a cell penetrating peptide, where Z is carbonyl or a direct bond,
• R9 is selected from the group consisting of an electron pair, hydrogen, C1-C6 alkyl, and aralkyl;
• each R10 is independently selected from hydrogen or methyl;
• and
• a moiety of formula (III):
• wherein:
• q is an integer from 0 to 2,
• R11 is selected from the group consisting of hydrogen, C1-C6 alkyl, aralkyl, and —C(═NH)NH2,
• R12 is selected from the group consisting of hydrogen, aralkyl, and C1-C6 alkyl, or
• R11 and R12 taken together with the nitrogen atom to which they are attached form a 5-7 membered ring where the ring is optionally substituted with a substituent selected from the group consisting of C1-C6 alkyl, phenyl, halogen, and aralkyl, and
• R13 is selected from the group consisting of an electron pair, hydrogen, C1-C6 alkyl, and aralkyl;
• R2 is selected from the group consisting of hydrogen, OH, a nucleotide, a cell-penetrating peptide, a moiety of formula:
• trityl, —C(═O)ORf, and acyl, wherein Rf is C1-C30 alkyl optionally substituted by one or more oxygen or hydroxyl moieties, or R2 is absent;
• R3 is selected from the group consisting of hydrogen, a C1-C6 alkyl, a nucleotide, a cell penetrating peptide, —C(═NH)NH2, trityl, —C(═O)ORg, acyl, and a moiety of formula:
• wherein
• Rg is C1-C30 alkyl optionally substituted by one or more oxygen or hydroxyl moieties;
• R4 is selected from the group consisting of an electron pair, hydrogen, a C1-C6 alkyl, and acyl
• R5 is independently selected from hydrogen or methyl;
• R6 and R7 is independently selected from hydrogen or -T3-NRcRdRe;
• and
• each of T1, T2, and T3 is independently an optional linker of up to 18 atoms in length comprising alkyl, alkoxy, or alkylamino groups, or combinations thereof, wherein the targeting sequence is complementary to a target region within intron 1 (SEQ ID. NO:
• 1) of a pre-mRNA of the human acid alpha-glucosidase (GAA) gene, and wherein the targeting sequence is selected from SEQ ID NOS:
• 4-6, 9, 45, 50, 54, 59-61, 68, 72, 73, and 77, wherein X is selected from uracil (U) or thymine (T).

A compound of formula (IV):

• or a pharmaceutically acceptable salt thereof, wherein:
• each Nu is a nucleobase which taken together form a targeting sequence;
• x is an integer from 18 to 25;
• each Y is O;
• each R1 is independently selected from the group consisting of:
• wherein at least one R1 is —N(CH3)2, and
• wherein the targeting sequence is selected from SEQ ID NOS:
• 4-6, 9, 45, 50, 54, 59-61, 68, 72, 73, and 77, wherein X is selected from uracil (U) or thymine (T).