Intranasal administration of guanidinylated aminoglycosides

• US 9,757,468 B2
• Filed: 03/13/2014
• Issued: 09/12/2017
• Est. Priority Date: 03/13/2013
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Esko, Jeffrey D., Tor, Yitzhak, Tong, Wenyong
• Primary Examiner(s): Tate, Chris R
• Assistant Examiner(s): Kosar, Aaron J
• Application Number:
  US14/774,257
• Publication Number:
  US 20160015822A1
• Time in Patent Office: 1,279 Days
• Field of Search: None
• CPC Class Codes: A61K 38/46 Hydrolases (3)
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/552 one of the codrug's components being an antibiotic
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/67 Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT
• CPC Class Codes: A61K 9/0043 Nose
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Y 302/01076 L-Iduronidase (3.2.1.76)
• CPC Class Codes: C12Y 310/01001 N-Sulfoglucosamine sulfohydrolase (3.10.1.1)

Abstract

This disclosure relates to intranasal administration of conjugates comprising guanidinylated aminoglycosides (“guanidinoglycosides”) and a polypeptide (e.g., an enzyme, antibody, or polypeptide growth factor). For example, such administration methods are useful for delivering a polypeptide to the brain and/or cerebrospinal fluid. Such methods are useful for treating a lysosomal storage disease through intranasal administration of a conjugate comprising one or more guanidinoglycosides and an enzyme useful for treating a lysosomal storage disease.

Claims

1. A method for treating a lysosomal storage disease affecting the brain of a patient in need thereof, the method comprising intranasally administering to the patient a therapeutically effective amount of a conjugate comprising one or more guanidinoglycosides and an enzyme, wherein the enzyme is useful for treating the lysosomal storage disease of the patient.

2. The method of claim 1, wherein the guanidinoglycoside is covalently bound to the enzyme, wherein the covalent bond is direct or optionally through a linker.

3. The method of claim 2, wherein the linker comprises one or more of a hydrocarbon moiety, a polyethylene glycol (PEG) moiety, an oligoamide moiety, an oligoester, and functionalized and/or chemically and enzymatically cleavable moieties.

4. The method of claim 1, wherein the enzyme is selected from the group consisting of:

α

-D-mannosidase;

N-aspartyl-β

-glucosaminidase;

acid lipase;

hexosaminidase A;

α

-galactosidase A;

β

-galactosidase;

ceramidase;

fucosidase;

β

-glucosidase;

N-acetylglucosamine-1-phosphotransferase;

galactocerebrosidase;

arylsulfatase A;

N-acetylglucosamine-1-phosphotransferase;

α

-L-iduronidase;

iduronate sulfatase;

heparan sulfamidase;

N-acetylglucosaminidase;

acetyl-CoA;

α

-glucosaminide acetyltransferase;

N-acetylglucosamine 6-sulfatase;

N-acetylgalactosamine-6-sulfate sulfatase;

N-acetylgalactosamine-4-sulfatase;

β

-glucuronidase;

hyaluronidase;

sialidase;

sulfatase;

sphingomyelinase;

acid α

-glucosidase;

β

-mannosidase;

cathepsin K;

β

-hexosaminidase A;

β

-hexosaminidase B;

α

-N-acetylgalactosaminidase;

sialin; and

hexosaminidase A.

5. The method of claim 4, wherein the enzyme is β

-glucosidase or α

-iduronidase.

6. The method of claim 1, wherein the lysosomal storage disease is selected from the group consisting of:

Activator Deficiency;

Alpha-mannosidosis;

Aspartylglucosaminuria;

Cholesteryl ester storage disease;

Chronic Hexosaminidase A Deficiency;

Cystinosis;

Danon disease;

Fabry disease;

Farber disease;

Fucosidosis;

Galactosialidosis;

Gaucher disease;

GM1 gangliosidosis;

I-Cell disease;

Infantile Free Sialic Acid Storage Disease;

Juvenile Hexosaminidase A deficiency;

Krabbe disease;

Metachromatic Leukodystrophy;

Mucopolysaccharidoses disorders;

Multiple sulfatase deficiency;

Niemann-Pick disease;

Neuronal Ceroid Lipofuscinoses;

Pompe disease;

Pycnodysostosis;

Sandhoff disease;

Schindler disease;

Salla disease;

Tay-Sachs; and

Wolman disease.

7. The method of claim 6, wherein the Mucopolysaccharidoses disorders are selected from the group consisting of:

Pseudo-Hurler polydystrophy;

Hurler Syndrome;

Scheie syndrome;

Hurler-Scheie syndrome;

Hunter syndrome;

Sanfilippo syndrome type A;

Sanfilippo syndrome type B;

Sanfilippo syndrome type C;

Sanfilippo syndrome type D;

Morquio type A;

Morquio type B;

Maroteaux-Lamy;

Sly syndrome; and

Natowicz syndrome Hyaluronidase deficiency.

8. The method of claim 7, wherein the Neuronal Ceroid Lipofuscinoses are selected from the group consisting of:

CLN6 disease;

Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disease;

Finnish Variant/Late Infantile CLN5;

Jansky-Bielschowsky disease/Late infantile CLN2/TPP1 Disease;

Kufs/Adult-onset NCL/CLN4 disease;

Northern Epilepsy/variant Late Infantile CLN8;

Santavuori-Haltia/Infantile CLN1/PPT disease; and

β

-mannosidosis.

9. The method of claim 1, wherein the guanidinoglycoside comprises an aminoglycoside antibiotic.

10. The method of claim 1, wherein the guanidinoglycoside is selected from the group consisting of guanidino-amikacin, guanidino-gentamicin, guanidino-kanamycin, guanidino-neomycin, guanidino-netilmicin, guanidino-O-2,6-diamino-2,6-dideoxy-beta-L-idopyranosyl (1→

3)-O-beta-D-ribofuranosyl (1→

5)-O-[2-amino-2-deoxy-alpha-D-glucopyranosyl (1→

4)]-2-deoxystreptamine, guanidino-paramycin, guanidino-streptomycin, guanidino-paromomycin, guanidine-dibekacin, guanidine-arbekacin, guanidino-isepamicin, guanidino-sisomicin, guanidine-ribostamycin, and guanidino-tobramycin.

11. The method of claim 1, wherein the enzyme has a molecular weight of greater than 27,500 Daltons.

12. A method for increasing the cellular uptake of an enzyme useful for treating a lysosomal storage disease in a patient, the method comprising:

a) coupling the enzyme to one or more guanidinoglycosides to form a conjugate; and

b) administering a therapeutically effective amount of the conjugate to the brain of the patient via intranasal administration.

13. The method of claim 12, wherein the enzyme has a molecular weight of greater than 27,500 Daltons.

14. A method for treating a CNS disorder in a patient, the method comprising administering to the brain of the patient via intranasal administration a therapeutically effective amount of a conjugate comprising one or more guanidinoglycosides and a therapeutically active compound or polypeptide useful for treating the CNS disorder.

15. The method of claim 14, wherein the therapeutically active compound or polypeptide has a molecular weight of greater than 27,500 Daltons.