Synthetic MBNL proteins for treatment of repeat expansion disease
AssigneeUniversity of Florida Research Foundation, Inc.
InventorsJohn A. Berglund, Melissa Hale
Life of this patent
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Abstract
Provided herein are compositions and methods related to treating repeat expansion diseases that feature the sequestration of Muscleblind-like (MBNL) proteins by the toxic repeat RNA transcripts within distinct nuclear foci that are expressed from the expanded repeat tracts. Certain compositions of synthetic MBLN proteins can be used to displace endogenous MBNL from the toxic RNAs or replace endogenous MBNL within the cell for normal function.
Claims15
A composition comprising a synthetic MBNL1 (Muscleblind-like protein 1) protein, wherein the synthetic MBNL1 protein comprises:
- a first zinc finger (ZF) domain comprising a first ZF motif and a second ZF motif,
- a second ZF domain comprising a third ZF motif and a fourth ZF motif, and nuclear localization signal (NLS);
- wherein the first ZF domain is linked to the second ZF domain by a linker, wherein the amino acid sequence of the first zinc finger domain is the same as the amino acid sequence of the second zinc finger domain;
- and
- wherein the first ZF domain is positioned towards the N-terminal of the synthetic MBNL1 protein relative to the second ZF domain wherein the amino acid sequence of the first ZF domain is SEQ ID NO:
- 1 or has at least 80% sequence identity to SEQ ID NO:
- 1 and the amino acid sequence of the second ZF domain is SEQ ID NO:
- 1 or has at least 80% sequence identity to SEQ ID NO:
- 1;
- or the amino acid sequence of the first ZF domain is SEQ ID NO:
- 2 or has at least 80% sequence identity to SEQ ID NO:
- 2 and the amino acid sequence of the second ZF domain is SEQ ID NO:
- 2 or has at least 80% sequence identity to SEQ ID NO:
- 2.
A composition comprising a synthetic MBNL1 protein, wherein the synthetic MBNL1 protein comprises:
- a first zinc finger (ZF) domain comprising a first ZF motif and a second ZF motif, a second ZF domain comprising a third ZF motif and a fourth ZF motif, and a cell penetrating peptide (CPP), or an RNA binding domain (RBD);
- wherein the first ZF domain is linked to the CPP or RBD by a linker sequence that is truncated relative to a wild-type MBNL1 linker sequence;
- wherein the amino acid sequence of the first zinc finger domain is the same as the amino acid sequence of the second zinc finger domain;
- and wherein the amino acid sequence of the first ZF domain is SEQ ID NO:
- 1 or has at least 80% sequence identity to SEQ ID NO:
- 1 and the amino acid sequence of the second ZF domain is SEQ ID NO:
- 1 or has at least 80% sequence identity to SEQ ID NO:
- 1;
- or the amino acid sequence of the first ZF domain is SEQ ID NO:
- 2 or has at least 80% sequence identity to SEQ ID NO:
- 2 and the amino acid sequence of the second ZF domain is SEQ ID NO:
- 2 or has at least 80% sequence identity to SEQ ID NO:
- 2.
Dependencies are inferred from the claim text.