Methods and compositions for treatment of myotubular myopathy using chimeric polypeptides comprising myotubularin 1(MTM1) polypeptides
AssigneeValerion Therapeutics, LLC
InventorDustin D. Armstrong
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Abstract
The present invention provides chimeric polypeptides comprising myotubularin 1 (MTMI) polypeptides and an internalizing moiety, wherein, the moiety can be an antibody, and is preferably monoclonal antibody 3E10, a functional variant or a fragment thereof. One aspect of the present invention provides compositions comprising these chimeric polypeptides together with a pharmaceutically acceptable carrier, and optionally, a further therapeutic agent. Another aspect of the present invention provides methods of treating Myotubular Myopathy comprising administering the polypeptides or compositions comprising the polypeptides to a subject in need.
Claims27
A chimeric polypeptide comprising:
- (i) a myotubularin (MTM1) polypeptide, or a bioactive fragment thereof;
- wherein the MTM1 polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:
- 1, and (ii) an internalizing moiety,
- wherein the chimeric polypeptide has phosphoinositide phosphatase activity;
- wherein said internalizing moiety is an antibody or antigen-binding fragment thereof,
- wherein said antibody or antigen-binding fragment thereof is a monoclonal antibody 3E10, or a variant thereof that retains the cell penetrating activity of 3E10, or an antigen-binding fragment of any of the foregoing.
A nucleic acid construct, comprising a nucleotide sequence that encodes a myotubularin (MTM1) polypeptide, or a bioactive fragment thereof, operably linked to a nucleotide sequence that encodes an internalizing moiety,
- wherein the nucleic acid construct encodes a chimeric polypeptide having phosphoinositide phosphatase activity;
- wherein the MTM1 polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:
- 1.
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 myotubularin (MTM1) polypeptide, or a bioactive fragment thereof;
- wherein the MTM1 polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:
- 1, and (ii) an internalizing moiety,
- wherein the chimeric polypeptide has phosphoinositide phosphatase activity;
- wherein said internalizing moiety is an antibody or antigen-binding fragment thereof,
- wherein said antibody or antigen-binding fragment thereof is a monoclonal antibody 3E10, or a variant thereof that retains the cell penetrating activity of 3E10, or an antigen-binding fragment of any of the foregoing.
Dependencies are inferred from the claim text.