Prolonging Survival of Platelets Using CMP-Sialic Acid, UDP-Galactose or Both
The present invention provides modified platelets having a reduced platelet clearance and methods for reducing platelet clearance. Also provided are compositions for the preservation of platelets. The invention also provides methods for making a pharmaceutical composition containing the modified platelets and for administering the pharmaceutical composition to a mammal to mediate hemostasis.
1 . A modified platelet comprising a plurality of modified glycan molecules on its surface, the modified platelets having increased circulation time following mammalian transplantation relative to unmodified platelets, wherein the modified glycan molecules on the surface of the platelet are sialylated at their termini with one or more glycan modifying agents, wherein the one or more glycan modifying agents comprise CMP-sialic acid, and optionally UDP-galactose.
2 . The modified platelet of claim 1 , wherein the modified glycan molecules on the surface of the platelet are galactosylated at their termini.
3 . The modified platelet of claim 1 , wherein the glycan molecules modified on the surface of the platelet are GP1bα molecules.
4 . The modified platelet of claim 3 , wherein one or more monosaccharides of the GP1bα molecules are modified at their termini.
5 . The modified platelet of claim 4 , wherein the one or more monosaccharides of the modified glycan is galactose.
6 . The modified platelet of claim 4 , wherein the one or more monosaccharides of the modified glycan is sialic acid.
7 . The modified platelet of claim 3 , wherein the one or more monosaccharides of the GP1bα molecules are modified with UDP-galactose and CMP-sialic acid.
8 . The modified platelet of claim 1 , wherein the modified platelet can be chilled with the one or more glycan modifying agents at a temperature in a range between about 0° C. and about 15° C.
9 . The modified platelet of claim 1 , wherein the modified platelet can be stored at room temperature with the one or more glycan modifying agents at a temperature ranging between about 18° C. and about 25° C.
10 . The modified platelet of claim 1 , wherein the modified platelet retains substantially normal hemostatic activity when transplanted into a mammal.
11 . The modified platelet of claim 1 , wherein the modified platelet when transplanted into a mammal, has a circulation half-life of at least about 5% greater than the circulation half-life of unmodified platelets.
12 . A platelet preparation, comprising a plurality of modified platelets having a plurality of modified glycan molecules on its surface, wherein the platelets are capable of being stored for between about 3 days and about 14 days, and the platelet preparation is suitable for administration to a human after storage without significant loss of hemostatic function or without a significant increase in platelet clearance in the human relative to unmodified platelets, wherein the modified glycan molecules on the surface of the platelet are sialylated at their termini with one or more glycan modifying agents, wherein the one or more glycan modifying agents comprise CMP-sialic acid, and optionally UDP-galactose.
13 . The modified platelet of claim 12 , wherein the modified glycan molecules on the surface of the platelet are galactosylated at their termini.
14 . The platelet preparation of claim 12 , wherein the glycan molecules modified on the surface of the platelet are GP1bα molecules.
15 . The platelet preparation of claim 14 , wherein one or more monosaccharides of the GP1bα molecules are modified at their termini.
16 . The platelet preparation of claim 15 , wherein the one or more monosaccharides of the modified glycan is galactose.
17 . The platelet preparation of claim 14 , wherein the one or more monosaccharides of the modified glycan is sialic acid.
18 . The platelet preparation of claim 14 , wherein the one or more monosaccharides of the GP1bα molecules are modified with UDP-galactose and CMP-sialic acid.
19 . The platelet preparation of claim 12 , wherein the platelet preparation can be chilled with the one or more glycan modifying agents at a temperature in a range between about 0° C. and about 15° C.
20 . The platelet preparation of claim 12 , wherein the platelet preparation can be stored at room temperature with the one or more glycan modifying agents at a temperature ranging between about 18° C. and about 25° C.
21 . The platelet preparation of claim 12 , wherein the modified platelet retains substantially normal hemostatic activity when transplanted into a mammal.
22 . The platelet preparation of claim 12 , wherein the modified platelet when transplanted into a mammal, has a circulation half-life of at least about 5% greater than the circulation half-life of unmodified platelets.
23 . A composition comprising the modified platelet of claim 1 , wherein the modified platelets are suitable for transplantation into a human.
24 . The composition of claim 23 , wherein the composition can be chilled with the one or more glycan modifying agents at a temperature in a range between about 0° C. and about 15° C.
25 . The composition of claim 23 , wherein the composition can be stored at room temperature with the one or more glycan modifying agents at a temperature ranging between about 18° C. and about 25° C.
26 . The composition of claim 23 , wherein the modified platelet retains substantially normal hemostatic activity when transplanted into a mammal.
27 . The composition of claim 23 , wherein the modified platelet when transplanted into a mammal, has a circulation half-life of at least about 5% greater than the circulation half-life of unmodified platelets.