Mutated Arylsulfatase a with Increased Stability

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This invention describes a genetically modified form of human Arylsulfatase A (ARSA) enzyme in which specific mutations, particularly at amino acid position E424, are introduced to significantly increase the enzyme's stability and half-life without sacrificing its activity. The invention also includes related nucleic acids, expression vectors, recombinant cells, and pharmaceutical compositions containing these mutated ARSA enzymes. These stable, active enzyme variants are especially useful for enzyme replacement or gene therapy in diseases caused by a deficiency of native ARSA, such as metachromatic leukodystrophy (MLD), a severe demyelinating disorder.

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• Enzyme replacement therapy for patients with metachromatic leukodystrophy (MLD).
• Gene therapy for treating genetic disorders characterized by ARSA deficiency.
• Development of more effective pharmaceutical formulations for lysosomal storage diseases involving ARSA.
• Engineering of recombinant cells for research or therapeutic enzyme production.
• Delivery of the enzyme to the central nervous system using modified ARSA variants (e.g., fusion with ApoE-II) for enhanced blood-brain barrier penetration.

BenefitsContent extracted from patent full text and abstract with AI.

• Increased protein stability and half-life of the enzyme, leading to less frequent dosing or improved efficacy.
• Enhanced enzymatic activity that persists over time, addressing the rapid degradation of wild-type enzymes.
• Reduced dosage requirements, potentially minimizing immune responses and side effects in patients.
• Improved distribution to the brain, essential for treating neurological symptoms of MLD and similar disorders.
• Compatibility with various delivery platforms, including direct enzyme replacement and gene or cell-based therapies.
• Reduced liver uptake and increased blood-brain barrier transcytosis for higher therapeutic concentration in the CNS.
• Flexibility to combine stability mutations with activity-enhancing mutations for superior therapeutic enzymes.

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Patent Abstract

The invention is based on the introduction of mutations into the amino acid sequence of human Arylsulfatase A (ASA or ARSA) in order to increase protein stability. The invention introduces amino acid mutations, such as deletions, substitutions or additions, into the C-terminal part of the human ARSA enzyme, in particular at a position around or at amino acid 424, which result in a sequence that does not comprise E424. Provided are further nucleic acids and vectors for the expression of the mutated ARSA of the invention, recombinant cells and pharmaceutical composition comprising the mutated ARSA, as well as its use in the treatment of diseases that are characterized by a reduced activity of endogenous ARSA.