Methods and compositions for treatment of myotonic dystrophy

A nucleic acid construct, comprising a nucleotide sequence that encodes a functional fragment of an MBNL polypeptide comprising four zinc finger motifs, operably linked to a nucleotide sequence that encodes a targeting moiety, wherein the targeting moiety comprises an antibody or antigen-binding fragment, which antibody or antigen-binding fragment comprises a heavy chain variable domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:

• 12 and a light chain variable domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:
• 14, or a humanized antibody or antigen-binding fragment thereof;
• wherein the nucleic acid construct encodes a chimeric polypeptide having MBNL biological activity and having the targeting activity of the targeting moiety;
• and wherein the chimeric polypeptide is capable of binding CUG repeats.

A method of delivering a chimeric polypeptide into a cell via an equilibrative nucleoside transporter (ENT2) pathway, comprising contacting a cell with a chimeric polypeptide, which chimeric polypeptide comprises (i) a functional fragment of an MBNL polypeptide and (ii) a targeting moiety which mediates transport across a cellular membrane via an ENT2 pathway, thereby delivering the chimeric polypeptide into the cell;

• wherein said functional fragment of said MBNL polypeptide comprises four zinc finger motifs, wherein the chimeric polypeptide is capable of binding CUG repeats;
• and wherein the targeting moiety comprises an antibody or antigen-binding fragment, which antibody or antigen-binding fragment comprises a heavy chain variable domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:
• 12 and a light chain variable domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:
• 14, or a humanized antibody or antigen binding fragment thereof.

A method of delivering a chimeric polypeptide into a muscle cell, comprising contacting a muscle cell with a chimeric polypeptide, which chimeric polypeptide comprises (i) a functional fragment of an MBNL polypeptide comprising four zinc finger motifs and (ii) a targeting moiety which promotes transport into muscle cells, thereby delivering the chimeric polypeptide into the muscle cell;

• wherein the chimeric polypeptide is capable of binding CUG repeats;
• and wherein the targeting moiety comprises an antibody or antigen-binding fragment, which antibody or antigen-binding fragment comprises a heavy chain variable domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:
• 12 and a light chain variable domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:
• 14, or a humanized antibody or antigen binding fragment thereof.

A method of increasing MBNL bioactivity in a muscle cell, comprising contacting a muscle cell with a chimeric polypeptide, which chimeric polypeptide comprises (i) a functional fragment of an MBNL polypeptide and (ii) a targeting moiety which promotes transport into muscle cells, thereby increasing MBNL bioactivity in the muscle cell;

• wherein said functional fragment of said MBNL polypeptide comprises four zinc finger motifs, and wherein the chimeric polypeptide is capable of binding CUG repeats;
• and wherein the targeting moiety comprises an antibody or antigen binding fragment, which antibody or antigen binding fragment comprises a heavy chain variable domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:
• 12 and a light chain variable domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:
• 14, or a humanized variant of said antibody or antigen binding fragment.