Cell therapy for the treatment of lysosomal storage disorders

• US 8,580,249 B2
• Filed: 04/05/2011
• Issued: 11/12/2013
• Est. Priority Date: 12/04/2003
• Status: Active Grant

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Blazar, Bruce, Tolar, Jakub, Verfaillie, Catherine M.
• Primary Examiner(s): Lankford, Blaine
• Application Number:
  US13/080,109
• Publication Number:
  US 20110243901A1
• Time in Patent Office: 952 Days
• Field of Search: None
• US Class Current: 424/93.7
• CPC Class Codes: A61K 35/48 Reproductive organs
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C12N 5/0607 Non-embryonic pluripotent stem cells, e.g. MASC induced pluripotent stem cells C12N5/0696

Abstract

The present invention relates to methods for providing lysosomal enzymes to a subject by administering stem cells, preferably Multipotent Adult Progenitor Cells (MAPCs). The invention further relates to methods for treating lysosomal storage disorders by administering stem cells.

Claims

1. A method for providing a lysosomal enzyme to a subject comprising administering stem cells to the subject, wherein the stem cells comprise isolated expanded human multipotent non-embryonic non-germ cells that can differentiate into at least one cell type of each of the endodermal, ectodermal, and mesodermal embryonic lineages and express telomerase, said cells having undergone at least 10-40 cell doublings in culture, and wherein the stem cells provide a lysosomal enzyme, wherein the stem cells naturally express a lysosomal enzyme.

4. The method of any of claims 1-3, wherein the non-embryonic, non-germ, non-embryonic germ cells express oct4.

5. The method of any of claims 1-3, wherein the lysosomal enzyme is selected from the group consisting of β

-galactosidase, hexosaminidase A, hexosaminidase B, GM₂-activator, arylsulfatase A, arylsulfatase B, galactosylceramidase, α

-galactosidase A, galactosamine-4-sulfatase, β

-glucosidase, sphingomyelinase, ceramidase, acid lipase, sulfatases, α

-L-iduronidase, iduronate-2-sulfate sulfatase, heparan sulfaminidase, N-acetyl-α

-glucosaminidase, α

-glucosaminide-N-acetyltransferase (acetyl CoA glucosamine-N-acetyltransferase), N-acetylglucosamine-6-sulfate sulfatase, N -acetylgalactosamine-6-sulfate sulfatase, α

-glucuronidase, hyaluronidase, cathepsin K, N-acetyl-α

-glucosaminidase, α

-fucosidase, α

-mannosidase, β

-mannosidase, sialic acid transporter, α

-N-acetylgalactosaminidase, α

-neuraminidase, cathepsin A, N-acetylglucosamine-l-phosphotransferase, α

-1,4-glucosidase, palmitoyl protein thioesterase, and tripeptidyl peptidase I.

6. The method of any of claim 4, wherein the lysosomal enzyme is selected from the group consisting of β

-galactosidase, hexosaminidase A, hexosaminidase B, GM₂-activator, arylsulfatase A, arylsulfatase B, galactosylceramidase, α

-galactosidase A, galactosamine-4-sulfatase, β

-glucosidase, sphingomyelinase, ceramidase, acid lipase, sulfatases, α

-L-iduronidase, iduronate-2-sulfate sulfatase, heparan sulfaminidase, N-acetyl-α

-glucosaminidase, α

-glucosaminide-N-acetyltransferase (acetyl CoA glucosamine-N-acetyltransferase), N-acetylglucosamine-6-sulfate sulfatase, N -acetylgalactosamine-6-sulfate sulfatase, α

-glucuronidase, hyaluronidase, cathepsin K, N-acetyl-α

-glucosaminidase, α

-fucosidase, α

-mannosidase, β

-mannosidase, sialic acid transporter, α

-N-acetylgalactosaminidase, α

-neuraminidase, cathepsin A, N-acetylglucosamine-1-phosphotransferase, α

-1,4-glucosidase, palmitoyl protein thioesterase, and tripeptidyl peptidase I.

7. The method of claim 5, wherein the enzyme is α

-L-iduronidase.

8. The method of claim 6, wherein the enzyme is α

-L-iduronidase.

9. The method of claim 1 or 3, wherein the subject has mucopolysaccharidosis.

10. The method of claim 9, wherein the mucopolysaccharidosis is Hurler'"'"'s Disease.

2. A method for treating a lysosomal storage disorder comprising administering stem cells to a subject having a lysosomal storage disorder, wherein the stem cells comprise isolated expanded human multipotent non-embryonic non-germ cells that can differentiate into at least one cell type of each of the endodermal, ectodermal, and mesodermal embryonic lineages and express telomerase, said cells having undergone at least 10-40 cell doublings in culture, and wherein the stem cells, following administration, naturally express an amount of lysosomal enzyme effective to treat said disorder.

11. The method of claim 2, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses, glycoproteinoses, mucolipidoses, glycogenosis type II and ceroid lipofuscinoses.

12. The method of claim 11, wherein the lysosomal storage disorder is a mucopolysaccharidosis.

13. The method of claim 12, wherein the mucopolysaccharidosis is Hurler'"'"'s Disease.

14. The method of claim 2, wherein the lysosomal storage disorder is selected from the group consisting of GM1 gangliosidosis, GM2 gangliosidosis variant B/B1 and variant 0, metachromatic leukodystrophy, Krabbe'"'"'s disease, Fabry'"'"'s disease, Gaucher'"'"'s disease, Niemann-Pick disease, Farber'"'"'s disease, Wolman'"'"'s disease, Austin'"'"'s disease, mucopolysaccharidoses type I, Scheie'"'"'s disease, Hurler-Scheie'"'"'s disease, Sanfilippo'"'"'s disease, Morquio'"'"'s disease, Maroteaux-Lamy'"'"'s disease, Sly'"'"'s disease, pycnodysostosis, aspartylglucosaminuria, fucosidosis, α

-mannosidosis, β

-mannosidosis, Schindler'"'"'s disease, Kanzaki'"'"'s disease, mucolipidoses type I, galactosialidosis, mucolipidoses, glycogenosis type II, Santavuori-Haltia disease, Jansky-Bielshowsky disease, Batten disease, Kufs disease, disease states characterized by mutations in the CLN5, CLN6, CLN7 and CLN8 loci, sialic acid storage diseases, Salla disease, and methylmalonic aciduria.

3. A method for modulating accumulation of a substrate in a subject comprising providing an amount of a lysosomal enzyme to the subject effective to modulate said accumulation, wherein the lysosomal enzyme is provided by stem cells administered to said subject, wherein the stem cells naturally express the lysosomal enzyme, and wherein the stem cells comprise isolated expanded human multipotent non-embryonic non-germ cells that can differentiate into at least one cell type of each of the endodermal, ectodermal, and mesodermal embryonic lineages and express telomerase, said cells having undergone at least 10-40 cell doublings in culture.

15. The method of claim 3, wherein the modulation comprises decreasing the substrate in a subject.

16. The method of claim 15, wherein the substrate is a glycosaminoglycan.

17. The method of claim 3, wherein the substrate is selected from the group consisting of dermatan sulfate, heparin sulfate, keratan sulfate, hyaluronic acid, sialic acid, GM₁-ganglioside, GM₂-ganglioside, galactosylceramide, sulfatide, galactosylsphingolipids, glucoceramide, ceramide, sphingomyelin, α

-mannoside, β

-mannoside, fucoside, aspartylglucosamine, N -acetylgalactosamine, glycogen, cholesterol ester, bone-derived peptides, and saposin.

18. A method for modulating accumulation of a substrate in a subject comprising providing α

-L-iduronidase to the subject in an amount effective to modulate said accumulation, wherein the α

-L-iduronidase is provided by cells administered to the subject, wherein the cells naturally express the α

-L-iduronidase, and wherein the cells are isolated expanded human multipotent non-embryonic non-germ cells that can differentiate into at least one cell type of each of the endodermal, ectodermal, and mesodermal lineages and express telomerase and oct3/4, said cells having undergone at least 10-40 cell doublings in culture, wherein said enzyme is provided by systemic injection, and wherein said subject has Hurler'"'"'s Disease.