Platelet Additive Solution Having a Beta-Galactosidase Inhibitor

Abstract

The present invention relates to a platelet additive solution (PAS) having an amount of one or more β-galactosidase inhibitors with or without an amount of one or more sialidase inhibitors, and optionally one or more glycan-modifying agents; and one or more of PAS components that include a salt, a citrate source, a carbon source, or any combination thereof.

What is claimed is: 
     
         1 . A method of storing platelets having a platelet surface, wherein active endogenous sialidase and β-galactosidase migrate to the platelet surface during storage, wherein sialic acid loss and galactose loss are reduced on the platelet surface of isolated platelets during storage, wherein the isolated platelets are obtained from one or more donors, the method comprises:
 a. contacting the isolated platelets with a platelet additive solution (PAS) that comprises:
 i. from about 0.1 mM to about 100 mM of one or more β-galactosidase inhibitors and from about 0.1 mM to about 100 mM of one or more sialidase inhibitors, and optionally an amount of one or more glycan-modifying agents, or a combination thereof; and 
 ii. PAS components that includes a salt, a phosphate source, a citrate source, a carbon source, an acetate source, or any combination thereof; 
 
 
       to thereby obtain a platelet composition, wherein cleavage by endogenous sialidase and β-galactosidase of sialic acid or galactose, respectively, is reduced, as compared to isolated platelets not subjected to Step a); and wherein once the platelet composition is transfused into a recipient, circulation time of platelets is increased, platelet clearance of the platelets is reduced, or both, as compared circulation time, platelet clearance, or both of platelets that have not been subjected to Step a). 
     
     
         2 . The method of  claim 1 , wherein the one or more sialidase inhibitors is selected from the group consisting of: fetuin; 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA); ethyl (3R,4R, 5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate); (2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid; (4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[(1R,2R)-3-hydroxy-2-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid; (1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4-(diaminomethylideneamino)-2-hydroxy-cyclopentane-1-carboxylic acid; a combination thereof; and a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the sialidase inhibitor is the sodium salt of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. 
     
     
         4 . The method of  claim 1 , wherein the one or more β-galactosidase inhibitors is selected from the group consisting of: 1-deoxygalactonojirimycin (DGJ); N-(n-butyl)deoxygalactonojirimycin; N-(n-nonyl)deoxygalactonojirimycin; 5-deoxy-L-arabinose; galactostatin bisulfate; 3′,4′,7-trihydroxyisoflavone; D-ribonolactone; N-octyl-4-epi-β-valienamine; phenylethyl B-D-thiogalactopyranoside; difluorotetrahydropyridothiazinone; 4-aminobenzyl 1-thio-β-D-galactopryranoside; a combination thereof; and a pharmaceutically acceptable salt thereof 
     
     
         5 . The method of  claim 1 , wherein the PAS is maintained at a pH ranging between about 6.4 and about 7.6. 
     
     
         6 . The method of  claim 1 , wherein the platelet composition is stored for a period of about 1 to about 21 days. 
     
     
         7 . The method of  claim 1 , wherein the platelet composition is stored at a temperature of between about 2° C. and about 25° C. 
     
     
         8 . The method of  claim 1 , further comprising cooling the platelet composition to a temperature below room temperature; storing the platelet composition for a period of time; and then rewarming the platelet composition back to room temperature. 
     
     
         9 . The method of  claim 1 , further comprising contacting the isolated platelets with the one or more β-galactosidase inhibitors and the one or more sialidase inhibitors, within a time period, wherein the time period is in a range between about 1 minute and about 8 hours. 
     
     
         10 . The method of  claim 1 , wherein the isolated platelets are mammalian platelets. 
     
     
         11 . The method of  claim 1 , wherein the β-galactosidase inhibitors is 1-deoxygalactonojirimycin (DGJ), and the sialidase inhibitor is the sodium salt of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. 
     
     
         12 . A method of storing a platelet composition, the method comprises:
 a. contacting the isolated platelets with:
 i. a PAS solution that comprises: 
 (a) about 0.1 mM to about 100 mM of one or more β-galactosidase inhibitors and from about 0.1 mM to about 100 mM of one or more sialidase inhibitors, and optionally an amount of one or more glycan-modifying agents, or a combination thereof; and 
 (b) one or more of PAS components that includes a salt, a citrate source, a carbon source, an acetate source, or any combination thereof; and 
 ii. plasma; 
   wherein active endogenous sialidase and β-galactosidase migrate to the platelet surface during storage, wherein cleavage by endogenous sialidase and β-galactosidase of sialic acid or galactose, respectively, is reduced, as compared to isolated platelets not subjected to PAS and wherein once the platelet composition is transfused into a recipient, circulation time of platelets is increased, platelet clearance of the platelets is reduced, or both, as compared circulation time, platelet clearance, or both of platelets that have not been subjected to PAS, wherein the platelet composition is maintained at a pH ranging between about 6.4 and about 7.6.   
     
     
         13 . The platelet composition of  claim 12 , wherein the plasma is present in an amount ranging between about 1% and about 50% by volume. 
     
     
         14 . The platelet composition of  claim 12 , wherein the platelet additive solution is present in an amount ranging between about 50% and about 99% by volume. 
     
     
         15 . A method of storing platelets having a platelet surface, wherein active endogenous sialidase and β-galactosidase migrate to the platelet surface during storage, wherein sialic acid loss and galactose loss are reduced on the platelet surface of isolated platelets during storage, wherein the isolated platelets are obtained from one or more donors, the method comprises:
 a. contacting the isolated platelets with a PAS that comprises:
 i. about 0.1 mM to about 100 mM of one or more β-galactosidase inhibitors and about 0.1 mM to about 100 mM of one or more sialidase inhibitors, and optionally an amount of one or more glycan-modifying agents, or a combination thereof; and 
 ii. PAS components that includes a salt, a citrate source, a carbon source, an acetate source, or any combination thereof. 
 
 
     
     
         16 . The method of  claim 15 , wherein the one or more sialidase inhibitors is selected from the group consisting of: fetuin; 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA); ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate); (2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid; (4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[(1R,2R)-3-hydroxy-2-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid; (1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4-(diaminomethylideneamino)-2-hydroxy-cyclopentane-1-carboxylic acid; a combination thereof; and a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 15 , wherein the sialidase inhibitor is the sodium salt of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. 
     
     
         18 . The method of  claim 15 , wherein the one or more β-galactosidase inhibitors is selected from the group consisting of: 1-deoxygalactonojirimycin (DGJ); N-(n-butyl)deoxygalactonojirimycin; N-(n-nonyl)deoxygalactonojirimycin; 5-deoxy-L-arabinose; galactostatin bisulfate; 3′,4′,7-trihydroxyisoflavone; D-ribonolactone; N-octyl-4-epi-β-valienamine; phenylethyl β-D-thiogalactopyranoside; difluorotetrahydropyridothiazinone; 4-aminobenzyl 1-thio-β-D-galactopryranoside; a combination thereof; and a pharmaceutically acceptable salt thereof 
     
     
         18 . The method of  claim 15 , wherein the PAS is maintained at a pH ranging between about 6.4 and about 7.6. 
     
     
         19 . The method of  claim 15 , wherein the platelet composition is stored for a period of about 1 to about 21 days. 
     
     
         20 . The method of  claim 15 , wherein the platelet composition is stored at a temperature of between about 2° C. and about 25° C. 
     
     
         21 . The method of  claim 15 , further comprising cooling the platelet composition to a temperature below room temperature; storing the platelet composition for a period of time; and then rewarming the platelet composition back to room temperature. 
     
     
         22 . The method of  claim 15 , further comprising contacting the isolated platelets with the one or more β-galactosidase inhibitors and the one or more sialidase inhibitors, within a time period, wherein the time period is in a range between about 1 minute and about 8 hours. 
     
     
         23 . The method of  claim 15 , wherein the isolated platelets are mammalian platelets. 
     
     
         24 . The method of  claim 15 , wherein the phosphate source is present in an amount ranging from about 5 mM to about 50 mM, and wherein the phosphate source is selected from the group consisting of sodium monophosphate, sodium diphosphate, sodium triphosphate, and a combination thereof 
     
     
         25 . The method of  claim 15 , wherein the citrate source is present in an amount ranging from about 2mM to about 20mM, and wherein the citrate source is selected from the group consisting of monosodium citrate, disodium citrate, trisodium citrate, citric acid, and a combination thereof 
     
     
         26 . The method of  claim 15 , wherein the carbon source is present in an amount ranging from about 0.5 mM to about 50 mM, and wherein the carbon source is selected from the group consisting of acetate, glucose, and sucrose. 
     
     
         27 . The method of  claim 15 , wherein the acetate source is present in an amount ranging from about 10 mM to about 50 mM, and wherein the acetate source is selected from the group consisting of sodium acetate, potassium acetate, magnesium acetate, and a combination thereof. 
     
     
         28 . The method of  claim 15 , wherein the salt is selected from the group consisting of a sodium source, a chloride source, a potassium source, a magnesium source, a calcium source, and a combination thereof. 
     
     
         29 . The method of  claim 15 , wherein the sodium source is selected from the group consisting of sodium chloride, sodium citrate, sodium acetate, sodium phosphate, and a combination thereof 
     
     
         30 . The method of  claim 15 , wherein the chloride source is selected from the group consisting of sodium chloride, magnesium chloride, potassium chloride, and a combination thereof. 
     
     
         31 . The method of  claim 15 , wherein the potassium source is selected from the group consisting of potassium chloride, potassium citrate, potassium acetate, potassium phosphate, potassium sulfate, and a combination thereof. 
     
     
         32 . The method of  claim 15 , wherein the magnesium source is selected from the group consisting of magnesium chloride, magnesium citrate, magnesium sulfate, and a combination thereof. 
     
     
         33 . The method of  claim 15 , wherein the calcium source is selected from the group consisting of calcium chloride, calcium acetate, calcium citrate, and a combination thereof. 
     
     
         34 . The method of  claim 15 , wherein the β-galactosidase inhibitors is 1-deoxygalactonojirimycin (DGJ), and the sialidase inhibitor is the sodium salt of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid.