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1. WO2006007560 - REMPLACEMENT DE PROTEINES CIBLEES POUR LE TRAITEMENT DE MALADIES LYSOSOMALES

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WHAT IS CLAIMED IS:
I. A mammalian lysosomal protein or an active fragment thereof which is attached to a targeting moiety, wherein the targeting moiety binds to a mammalian cell surface molecule and allows internalization of said mammalian lysosomal protein or active fragment by the mammalian cell via a non-clathrin pathway.
2. The mammalian lysosomal protein or active fragment of claim 1 which is covalently attached to said targeting moiety and said protein or said fragment
3. The mammalian lysosomal protein or active fragment of claim 2 which is a fusion protein comprising said targeting moiety and said protein or said fragment.
4. The mammalian lysosomal protein or active fragment of claim 3 in which the targeting moiety is N- terminal to said protein or said fragment.
5. The mammalian lysosomal protein or active fragment of claim 3 in which the targeting moiety is C-terminal to said protein or said fragment.
6. The mammalian lysosomal protein or active fragment of claim 2 which is conjugated to said targeting moiety.
7. The mammalian lysosomal protein or active fragment of claim 6 which is conjugated to said targeting moiety by chemical cross-linking.
8. The mammalian lysosomal protein or active fragment of any one of claims 1-7, wherein the targeting moiety is an antibody or a non-immunoglobulin polypeptide.

9. The mammalian lysosomal protein or active fragment of any one of claims 1-7, wherein the targeting moiety binds to an extracellular portion of ICAM- 1 or PECAM- 1.

10. The mammalian lysosomal protein or active fragment of claim 9, wherein the targeting moeity is an antibody.
I 1. The mammalian lysosomal protein or active fragment of any one of claims 1 -7 which is an α-N-acetylgalactosaminidase, acid lipase, α-galactosidase,
glucocerebrosidase, α-L-iduronidase, iduronate sulfatase, α-mannosidase, α-L-fucosidase, sialidase, or acid sphingomyelinase.

12. The mammalian lysosomal protein or active fragment of any one of claims 1-7 in which the mammalian lysosomal protein is acid sphingomyelinase and the targeting moiety binds to an extracellular portion of ICAM-I or PECAM-I.
13. The mammalian lysosomal protein or active fragment of any one of claims 1-7 which is at least 95% pure.
14. A particle comprising the mammalian lysosomal protein or active fragment of any one of claims 1-7.
15. A particle comprising the mammalian lysosomal protein or active fragment of claim 8.
16. A particle comprising the mammalian lysosomal protein or active fragment claim 9.
17. A particle comprising the mammalian lysosomal protein or active fragment of claim 11.
18. A particle comprising the mammalian lysosomal protein or active fragment of claim 12.
19. A particle comprising the mammalian lysosomal protein or active fragment of claim 13.
20. The particle of claim 14 which is 50 nm to 10 μm in size.
21. The particle of claim 20 which is 200-300 nm in size.
22. The particle of claim 14 which is a synthetic carrier particle.
23. The particle of claim 14 which is a liposome, a microbubble, a dendrimer, or a micelle.
24. The particle of claim 22 in which the synthetic carrier particle is coupled to, loaded into, loaded onto or coated with said targeting moiety.
25. A pharmaceutical composition comprising (a) the mammalian lysosomal protein or an active fragment of any one of claims 1-7 and (b) a pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising (a) the mammalian lysosomal protein or an active fragment of claim 13 and (b) a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising (a) the particle of claim 14 and (b) a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising (a) the particle of claim 20 and (b) a pharmaceutically acceptable carrier.
29. A method for treating a subject in need of lysosomal protein replacement therapy, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 25.
30. A method for treating a subject in need of lysosomal protein replacement therapy, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 26.
31. A method for treating a subject in need of lysosomal protein replacement therapy, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 27.
32. A method for trealing a subject in need of lysosomal protein replacement therapy, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 28.
33. The method of claim 29, wherein the subject has Pompe Disease, GMl gangliosidosis, Tay-Sachs disease, GM2 gangliosidosis, Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C, Niemann-Pick disease type D, Farber disease, Wolman disease, Hurler Syndrome, Scheie Syndrome, Hurler-Scheie Syndrome, Hunter Syndrome, Sanfilippo A Syndrome, Sanfilippo B Syndrome, Sanfilippo C Syndrome, Sanfilippo D Syndrome, Morquio A disease, Morquio B disease, Maroteaux-Lamy disease, Sly Syndrome, α-mannosidosis, β-mannosidosis, fucosidosis, aspartylglucosaminuria, sialidosis, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Goldberg Syndrorme, Schindler disease, cystinosis, Salla disease, infantile sialic acid storage disease, Batten disease, infantile neuronal ceroid lipofuscinosis, or prosaposin.
34. The method of claim 30, wherein the subject has Pompe Disease, GMl gangliosidosis, Tay-Sachs disease, GM2 gangliosidosis, Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C, Niemann-Pick disease type D, Farber disease, Wolman disease, Hurler Syndrome, Scheie Syndrome, Hurler-Scheie Syndrome, Hunter Syndrome, Sanfilippo A Syndrome, Sanfϊlippo B Syndrome, Sanfilippo C Syndrome, Sanfilippo D Syndrome, Morquio A disease, Morquio B disease, Maroteaux-Lamy disease, Sly Syndrome, α-mannosidosis, β-mannosidosis, fucosidosis, aspartylglucosaminuria, sialidosis, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Goldberg Syndrorme, Schindler disease, cystinosis, Salla disease, infantile sialic acid storage disease, Batten disease, infantile neuronal ceroid lipofuscinosis, or prosaposin.
35. The method of claim 31 , wherein the subject has Pompe Disease, GMl gangliosidosis, Tay-Sachs disease, GM2 gangliosidosis, Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C, Niemann-Pick disease type D, Farber disease, Wolman disease, Hurler Syndrome, Scheie Syndrome, Hurler-Scheie Syndrome, Hunter Syndrome, Sanfilippo A Syndrome, Sanfilippo B Syndrome, Sanfilippo C Syndrome, Sanfilippo D Syndrome, Morquio A disease, Morquio B disease, Maroteaux-Lamy disease, Sly Syndrome, α-mannosidosis, β-mannosidosis, fucosidosis, aspartylglucosaminuria, sialidosis, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Goldberg Syndrorme, Schindler disease, cystinosis, Salla disease, infantile sialic acid storage disease, Batten disease, infantile neuronal ceroid lipofuscinosis, or prosaposin.
36. The method of claim 32, wherein the subject has Pompe Disease, GMl gangliosidosis, Tay-Sachs disease, GM2 gangliosidosis, Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C, Niemann-Pick disease type D, Farber disease, Wolman disease, Hurler Syndrome, Scheie Syndrome, Hurler-Scheie Syndrome, Hunter Syndrome, Sanfilippo A Syndrome, Sanfilippo B Syndrome, Sanfilippo C Syndrome, Sanfilippo D Syndrome, Morquio A disease, Morquio B disease, Maroteaux-Lamy disease, Sly Syndrome, α-mannosidosis, β-mannosidosis, fucosidosis, aspartylglucosaminuria, sialidosis, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Goldberg Syndrorme, Schindler disease, cystinosis, Salla disease, infantile sialic acid storage disease, Batten disease, infantile neuronal ceroid lipofuscinosis, or prosaposin.
37. A nucleic acid comprising a nucleotide sequence encoding the mammalian lysosomal protein or active fragment of any one of claims 3-5.
38. The nucleic acid of claim 37 in which the nucleotide sequence is operably linked to a promoter.
39. A recombinant cell which comprises in its genome the nucleic acid of claim 37.

40. A recombinant cell which comprises in its genome the nucleic acid of claim 38.

41. A method for producing the mammalian lysosomal protein or active fragment of any one of claims 3-5, comprising (a) culturing the recombinant cell of claim 39 under conditions in which the mammalian lysosomal protein or active fragment is expressed and (b) recovering the expressed mammalian lysosomal protein or active fragment.

42. A method for producing the mammalian lysosomal protein or active fragment of any one of claims 3-5, comprising (a) culturing the recombinant cell of claim 40 under conditions in which the mammalian lysosomal protein or active fragment is expressed and (b) recovering the expressed mammalian lysosomal protein or active fragment.

43. The method of claim 41, in which the recombinant cell is a mammalian cell in culture.
44. The method of claim 42, in which the recombinant cell is a mammalian cell in culture.