Intranasal administration of guanidinylated aminoglycosides
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.
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.