COMPOUND AND METHOD FOR TREATING MYOTONIC DYSTROPHY
First Claim
1. An antisense compound for use in treating myotonic dystrophy DM1 or DM2, comprisingan antisense oligonucleotide having 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′
- UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, andconjugated to the oligonucleotide, a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine;
B is β
-alanine; and
each X is —
C(O)—
(CH2)n—
NH—
, where n is 4-6.where the compound is effective to selectively block the sequestration of at least one of muscleblind-like 1 protein (MBNL1) and CUGBP in heart and quadricep muscle in a myotonic dystrophy animal model.
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Abstract
An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is β-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
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Citations
22 Claims
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1. An antisense compound for use in treating myotonic dystrophy DM1 or DM2, comprising
an antisense oligonucleotide having 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′ - UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, and
conjugated to the oligonucleotide, a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine;
B is β
-alanine; and
each X is —
C(O)—
(CH2)n—
NH—
, where n is 4-6.where the compound is effective to selectively block the sequestration of at least one of muscleblind-like 1 protein (MBNL1) and CUGBP in heart and quadricep muscle in a myotonic dystrophy animal model. - View Dependent Claims (2, 3, 4, 5, 6, 7)
- UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, and
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8. A method of targeting a systemically administered antisense oligonucleotide to heart muscle tissue in a mammalian subject, where the oligonucleotide is directed against the polyCUG or polyCCUG repeats in the 3′
- UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, comprising
conjugating to the oligonucleotide, a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine;
B is β
-alanine; and
each X is independently a neutral linear amino acid —
C(O)—
(CH2)n—
NH—
, where n is 4-6. - View Dependent Claims (9, 10, 11, 12, 13)
- UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, comprising
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14. A method of treating mytonic dystrophy DM1 or DM2 in a mammalian subject, comprising
administering to the subject, an antisense compound comprising an antisense oligonucleotide having 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′ - UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, and conjugated to the oligonucleotide, a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine;
B is β
-alanine; and
each X is —
C(O)—
(CH2)n—
NH—
, where n is 4-6, andrepeating said administering at least once every one week to 3 months. - View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22)
- UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively, and conjugated to the oligonucleotide, a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine;
Specification