Mutated arylsulfatase a
AssigneeRheinische Friedrich-Wilhelms-Universität Bonn
InventorsUlrich Matzner, Volkmar Gieselmann
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Abstract
The present invention pertains to a novel treatment of pathologies caused by an increased synthesis or accumulation of sulfolipids such as sulfatide. The invention provides mutated arylsulfatase A (ARSA or ASA, EC 3.1.6.8) enzymes with increased activity towards sulfatide metabolization. The invention provides nucleic acids encoding the mutant ARSA, the use of the proteins and nucleic acids, as well as pharmaceutical compositions comprising them, in the treatment of lysosomal storage disorders (LSDs) such as metachromatic leukodystrophy (MLD).
Claims17
A mutated arylsulfatase A (ARSA) enzyme, comprising an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1 outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between the variable domains v4 to v6 of SEQ ID NO:
- 1.
An isolated nucleic acid comprising a sequence coding for a mutated arylsulfatase A (ARSA) enzyme, wherein the mutated ARSA enzyme comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1 outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between the variable domains v4 to v6 of SEQ ID NO:
- 1.
A recombinant cell comprising a mutated ARSA enzyme, or a nucleic acid or vector encoding the mutated ARSA enzyme, wherein the mutated ARSA enzyme comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1 outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between the variable domains v4 to v6 of SEQ ID NO:
- 1.
A pharmaceutical composition comprising a mutated ARSA enzyme, or a nucleic acid or vector encoding the mutated ARSA enzyme, or a recombinant cell comprising the mutated ARSA enzyme or comprising the nucleic acid or vector, wherein the mutated ARSA enzyme comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1 outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between the variable domains v4 to v6 of SEQ ID NO:
- 1.
A method for the treatment of a disease in a subject, the method comprising administering to the subject a mutated ARSA enzyme, or a nucleic acid or vector encoding the mutated ARSA enzyme, wherein the mutated ARSA enzyme comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1 outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between residues 100 and 400 variable domains v4 to v6 of SEQ ID NO:
- 1.
A method for designing and/or producing a mutated ARSA enzyme comprising the steps of
- (a) providing a parent ARSA enzyme-encoding nucleic acid sequence which encodes a parent ARSA enzyme having an amino acid sequence with 100% sequence identity to SEQ ID NO:
- 1,
- (b) introducing into said parent ARSA enzyme-encoding nucleic acid sequence at least one mutation in variable domains v4 to v6 including a M202V mutation, thereby generating a mutated ARSA enzyme encoding nucleic acid sequence, wherein the mutated ARSA enzyme encoding nucleic acid sequence encodes a mutated ARSA enzyme comprising a mutated ARSA enzyme amino acid sequence, that, when aligned to the sequence of SEQ ID NO:
- 1, comprises the M202V mutation compared to the sequence of SEQ ID NO:
- 1 between variable domains v4 to v6, and wherein said M202V mutation constitutes a mutation when compared to the amino acid sequence of the parent ARSA enzyme.
A mutated arylsulfatase A (ARSA) enzyme, comprising a human ARSA amino acid sequence outside of variable domains v4 to v6, wherein the mutated ARSA enzyme amino acid sequence when aligned to the sequence of SEQ ID NO:
- 1, comprises a M202V mutation compared to the sequence between the variable domains v4 to v6 of SEQ ID NO:
- 1.
Dependencies are inferred from the claim text.