Treatment of mucopolysaccharidosis II with recombinant human iduronate-2 sulfatase (IDS) produced by human neural or glial cells

AU2025200141B2Pending Publication Date: 2026-08-06REGENXBIO INC
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Patent Information

Authority / Receiving Office
AU · AU
Patent Type
Applications
Current Assignee / Owner
REGENXBIO INC
Filing Date
2025-01-09
Publication Date
2026-08-06

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Abstract

Abstract: Compositions and methods are described for the delivery of recombinant human iduronate-2- sulfatase (IDS) produced by human neuronal or glial cells to the cerebrospinal fluid of the central nervous system (CNS) of a human subject diagnosed with mucopolysaccharidosis II (MPS II). Abstract: Compositions and methods are described for the delivery of recombinant human iduronate-2- sulfatase (IDS) produced by human neuronal or glial cells to the cerebrospinal fluid of the central nervous system (CNS) of a human subject diagnosed with mucopolysaccharidosis II (MPS II). 20 25 20 01 41 09 J an 2 02 5 2 0 2 5 2 0 0 1 4 1 0 9 J a n 2 0 2 5
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Claims

1. Glycosylated recombinant human iduronate-2-sulfatase (IDS) precursor produced by human neuronal or human glial cells.

2. The glycosylated recombinant human IDS precursor of claim 1, which is about 90 kDa as measured by polyacrylamide gel electrophoresis.

3. The glycosylated recombinant human IDS precursor of claim 1, which is about 90 kDa as measured by polyacrylamide gel electrophoresis, contains a formylglycine, is a2,6-sialylated, does not contain detectable NeuGc, does not contain detectable a-Gal antigen, and / or is mannose-6-phosphorylated.

4. The glycosylated recombinant human IDS precursor of any one of claims 1 to 3, which is secreted from a depot of cells in the central nervous system genetically engineered to secrete said human IDS glycoprotein precursor.

5. The glycosylated recombinant human IDS precursor of claim 4, in which the depot is formed in a human subject’s brain.

6. The glycosylated recombinant human IDS precursor of any one of claims 1 to 5, in which the human neuronal or human glial cells are deficient in IDS activity.

7. The glycosylated recombinant human IDS precursor of any one of claims 1 to 6, in which the glycosylated recombinant human IDS precursor comprises the amino acid sequence of SEQ ID NO. 1.

8. A method for treating a human subject diagnosed with mucopolysaccharidosis type II (MPS II), comprising delivering to the cerebrospinal fluid (CSF) of said human subject a therapeutically effective amount of a glycosylated recombinant human iduronate-2-sulfatase (IDS) precursor produced by human neuronal or human glial cells.2025200141   09 Jan 20259. The method of claim 8, wherein the glycosylated recombinant human IDS precursor is about 90 kDa as measured by polyacrylamide gel electrophoresis.

10. The method of claim 8, wherein the glycosylated recombinant human IDS precursor is about 90 kDa as measured by polyacrylamide gel electrophoresis, contains a formylglycine, is a2,6-sialylated, does not contain detectable NeuGc, does not contain detectable a-Gal antigen, and / or is mannose-6-phosphorylated11. The method of any one of claims 8 to 10, wherein the glycosylated recombinant human IDS precursor is secreted from a depot of cells in the central nervous system genetically engineered to secrete said glycosylated recombinant human IDS precursor12.  The method of claim 11, in which the depot is formed in a human subject’s brain.

13. The method of any one of claims 8 to 12, in which the human subject is deficient inIDS activity.

14. The method of any one of claims 8 to 13, in which the glycosylated recombinant human IDS precursor comprises the amino acid sequence of SEQ ID NO. 1.

15. A method for treating a human subject diagnosed with MPS II, comprising administering to the CSF of said human subject a recombinant nucleotide expression vector encoding human IDS, wherein said recombinant nucleotide expression vector when used to transduce a primary human neuronal cell in culture directs the expression of a secreted glycosylated human IDS precursor that is about 90 kDa as measured by polyacrylamide gel electrophoresis, contains a formylglycine, is a2,6-sialylated, does not contain detectable NeuGc, does not contain detectable a-Gal antigen, and / or is mannose-6-phosphorylated.

16. A method for treating a human subject diagnosed with MPS II, comprising administering to the CSF of said human subject a recombinant nucleotide expression vector encoding human IDS, so that a depot is formed in the human central nervous system that secretes2025200141   09 Jan 2025a glycosylated human IDS precursor that is about 90 kDa as measured by polyacrylamide gel electrophoresis, contains a formylglycine, is a2,6-sialylated, does not contain detectable NeuGc, does not contain detectable a-Gal antigen, and / or is mannose-6-phosphorylated.

17. The method of claim 16, wherein secretion of said glycosylated human IDS precursor is confirmed by transducing a human neuronal cell line with said recombinant nucleotide expression vector in cell culture.

18. The method of claim 16 or 17, wherein secretion of said glycosylated human IDS precursor is confirmed in the presence and absence of mannose-6-phosphate.

19. The metho of any one of claims 15 to 18, in which the human IDS comprises the amino acid sequence of SEQ ID NO 120. The method of any one of claims 15 to 19, wherein the recombinant nucleotide expression vector comprises a neuron-specific promoter that controls the expression of the glycosylated human IDS precursor in human neuronal cells or a glial cell-specific promoter that controls the expression of the glycosylated human IDS precursor in human glial cells.

21. The method of any one of claims 15 to 20, wherein the recombinant nucleotide expression vector encodes a leader peptide that ensures proper co- and post-translational processing of the glycosylated human IDS precursor in human neuronal cells or human glial cells22. The method of any one of claims 15 to 21, wherein the recombinant nucleotide expression vector is an AAV vector.

23. The method of claim 22, wherein the recombinant nucleotide expression vector is a replication defective AAV vector.2025200141   09 Jan 202524. The method of claim 22 or 23, wherein the recombinant nucleotide expression vector is an AAV9 or AAVrhlO vector.

25. The method of any one of claims 15 to 24, wherein the recombinant nucleotide expression vector is delivered to the CSF of the human subject by intrathecal, intracerebroventricular, lumbar puncture or intranasal administration.

26. The method of any one of claims 15 to 25, wherein the human subject is deficient in IDS activity.

27. A method for treating a human subject diagnosed with MPS II, comprising administering to the CSF of said human subject a formulation comprising a recombinant nucleotide expression vector encoding human IDS, wherein the formulation is suitable for administration to the CSF of human brain, so that a depot is formed in the human central nervous system that secretes a glycosylated human IDS precursor that is about 90 kDa as measured by polyacrylamide gel electrophoresis, contains a formylglycine, is a2,6-sialylated, does not contain detectable NeuGc, does not contain detectable a-Gal antigen, and / or is mannose-6-phosphorylated

Citation Information

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