Method and composition for treating arginase 1 deficiency
A method and composition to treat a subject with arginase 1 (ARG1) deficiency (ARG1-D) and to rapidly reduce the levels of at least one of arginine and/or a guanidino compound in the subject.
1 . A method for reducing a plasma level of at least one compound selected from the group consisting of: arginine, N-α-acetylarginine (NAArg), argininic acid (ArgA), α-keto-δ-guanidinovaleric acid (GVA), guanidinoacetic acid (GAA), to a normal level in a subject with Arginase 1 (ARG1) deficiency (ARG1-D) comprising administering to the subject a composition comprising a therapeutically effective amount of a pegylated arginase, wherein the pegylated arginase is administered intravenously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 1.00 mg/kg.
2 . The method of claim 1 , wherein the pegylated arginase is administered intravenously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 0.50 mg/kg.
3 . The method of claim 2 , wherein the pegylated arginase is administered intravenously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 0.25 mg/kg.
4 . The method of any one of claims 1-3 , wherein the pegylated arginase is pegzilarginase.
5 . The method of claim 1 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 3 days after initial administration of the pegylated arginase.
6 . The method of claim 1 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 2 days after initial administration of the pegylated arginase.
7 . The method of claim 1 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 1 day after initial administration of the pegylated arginase.
8 . The method of claim 1 , wherein the dosage of the pegylated arginase administered to the subject is sufficient to reduce by at least 2 fold a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, wherein the plasma level is assayed about 24 to 48 hours after administration of the pegylated arginase.
9 . A method for reducing a plasma level of at least one compound selected from the group consisting of: arginine, N-α-acetylarginine (NAArg), argininic acid (ArgA), α-keto-δ-guanidinovaleric acid (GVA), guanidinoacetic acid (GAA), to a normal level in a subject with Arginase 1 (ARG1) deficiency (ARG1-D) comprising administering to the subject a composition comprising a therapeutically effective amount of a pegylated arginase, wherein the pegylated arginase is administered subcutaneously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 1.00 mg/kg.
10 . The method of claim 9 , wherein the pegylated arginase is administered subcutaneously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 0.50 mg/kg.
11 . The method of claim 10 , wherein the pegylated arginase is administered subcutaneously initially at a dosage of about 0.1 mg/kg, and weekly thereafter either subcutaneously or intravenously at a dosage of about 0.01 mg/kg to about 0.25 mg/kg.
12 . The method of any one of claims 9-11 , wherein the pegylated arginase is pegzilarginase.
13 . The method of claim 9 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 3 days after initial administration of the pegylated arginase.
14 . The method of claim 9 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 2 days after initial administration of the pegylated arginase.
15 . The method of claim 9 , wherein a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, is reduced to a normal level in the subject in less than 1 day after initial administration of the pegylated arginase.
16 . The method of claim 9 , wherein the dosage of the pegylated arginase administered to the subject is sufficient to reduce by at least 2 fold a plasma level of at least one compound selected from the group consisting of: ArgA, NAArg, GVA, GAA, and arginine, wherein the plasma level is assayed about 24 to 48 hours after administration of the pegylated arginase.
17 . The method of claim 1 , wherein the subject has a minimal clinically important difference (MCID) of greater than 1 after 9 days of treatment.
18 . The method of claim 17 , wherein the plasma level of arginine is correlated with the MCID.
19 . The method of claim 1 , wherein the pegylated arginase has the sequence of SEQ ID NO: 13.
20 . The method of claim 19 , wherein the pegylated arginase lacks the N-terminal methionine.
21 . The method of claim 9 , wherein the pegylated arginase has the sequence of SEQ ID NO: 13.
22 . The method of claim 21 , wherein the pegylated arginase lacks the N-terminal methionine.