Methods and compositions for the treatment of metabolic disorders

Abstract

The present invention is directed to a novel methods and compositions for the therapeutic intervention in hyperphenylalaninemia. More specifically, the specification describes methods and compositions for treating various types of phenylketonurias using compositions comprising BH4. Combination therapies of BH4 and other therapeutic regimens are contemplated.

What is claimed is: 
     
         1 . A method for treating classic severe phenylketonuria (PKU) in a subject comprising administering to said subject a protein-restricted diet in combination with a composition comprising tetrahydrobiopterin (BH4) or a precursor or derivative thereof, wherein the combined administration of the protein-restricted diet and BH4 is effective to lower the phenylalanine concentration in the plasma of said subject as compared to said concentration in the absence of said combined administration. 
     
     
         2 . The method of  claim 1 , wherein said subject does not have a deficiency in BH4 homeostasis. 
     
     
         3 . The method of  claim 1 , wherein said subject has a plasma phenylalanine concentration of greater than 1000 μM in the absence of a therapeutic regimen. 
     
     
         4 . The method of  claim 3 , wherein said combined administration decreases the plasma phenylalanine concentration of said subject to less than 600 μM. 
     
     
         5 . The method of  claim 3 , wherein said combined administration decreases the plasma phenylalanine concentration of said subject to less than 500 μM. 
     
     
         6 . The method of  claim 3 , wherein said combined administration decreases the plasma phenylalanine concentration of said subject to 360 μM±15 μM. 
     
     
         7 . The method of  claim 1 , wherein said BH4 is administered in an amount of between about 1 mg/kg to about 30 mg/kg. 
     
     
         8 . The method of  claim 7 , wherein said BH4 is administered in an amount of between about 5 mg/kg to about 30 mg/kg. 
     
     
         9 . The method of  claim 7 , wherein said BH4 is administered in a single daily dose. 
     
     
         10 . The method of  claim 7 , wherein said BH4 is administered in multiple doses on a daily basis. 
     
     
         11 . The method of  claim 1 , wherein said BH4 is administered on a daily basis until the plasma phenylalanine concentration of said subject is decreased to less than 360 μM. 
     
     
         12 . The method of  claim 11 , wherein the plasma phenylalanine concentration of said subject is monitored on a daily basis and said BH4 is administered when a 10% increase in plasma phenylalanine concentration is observed. 
     
     
         13 . The method of  claim 1 , wherein said BH4 is administered as a stabilized crystallized form. 
     
     
         14 . The method of  claim 9 , wherein said stabilized crystallized form of BH4 comprises at least 99.5% pure 6R BH4. 
     
     
         15 . The method of  claim 1 , wherein said BH4 precursor is dihydrobiopterin (BH2). 
     
     
         16 . The method of  claim 1 , wherein said BH4 precursor is sepiapterin. 
     
     
         17 . The method of  claim 1 , wherein said protein-restricted diet is a phenylalanine-restricted diet wherein the total phenylalanine is restricted to less than 600 mg per day. 
     
     
         18 . The method of  claim 1 , wherein said protein-restricted diet is a phenylalanine-restricted diet wherein the total phenylalanine is restricted to less than 300 mg per day. 
     
     
         19 . The method of  claim 1 , wherein said protein-restricted diet is supplemented with tyrosine. 
     
     
         20 . The method of  claim 1 , wherein said protein-restricted diet comprises a high content of one or more amino acids selected from valine, isoleucine and leucine. 
     
     
         21 . The method of  claim 1 , wherein said BH4 is administered orally. 
     
     
         22 . The method of  claim 1 , wherein said subject has been diagnosed as having a mutant phenylalanine hydroxylase (PAH). 
     
     
         23 . The method of  claim 22 , wherein said mutant PAH comprises a mutation in the catalytic domain of PAH. 
     
     
         24 . The method of  claim 22 , wherein said mutation comprises one or more mutations selected from the group consisting of F39L, L48S, I65T, R68S, A104D, S110C, D129G, E178G, V190A, P211T, R241C, R261Q, A300S, L308F, A313T, K320N, A373T, V388M E390G, A395P, P407S, and Y414C. 
     
     
         25 . The method of  claim 1 , wherein said subject is subject does not manifest symptoms of L-dopa neurotransmitter deficiency. 
     
     
         26 . The method of  claim 1 , wherein said protein-restricted diet comprises a protein supplement and said BH4 is provided in the same composition as said protein supplement. 
     
     
         27 . A method for the treating a pregnant female having hyperphenylalaninemia (HPA) comprising administering to said subject a protein-restricted diet in combination with a composition comprising tetrahydrobiopterin (BH4) or a precursor or derivative thereof, wherein the combined administration of the protein-restricted diet and BH4 is effective to lower the phenylalanine concentration in the plasma of said subject as compared to said concentration in the absence of said combined administration. 
     
     
         28 . The method of  claim 27 , wherein said subject has a plasma phenylalanine concentration of greater than 180 μM but less than 600 μM. 
     
     
         29 . The method of  claim 27 , wherein said subject has a plasma phenylalanine concentration of greater than 600 μM but less than 1200 μM. 
     
     
         30 . The method of  claim 27 , wherein said subject has a plasma phenylalanine concentration of greater than 1200 μM. 
     
     
         31 . The method of any of  claims 1  to  30 , wherein said composition further comprises a folate. 
     
     
         32 . The method of  claim 31 , wherein said folate comprises a tetrahydrofolate selected from the group consisting of tetrahydrofolate is 5-formyl-(6S)-tetrahydrofolic acid and salts thereof, 5-methyl-(6S)-tetrahydrofolic acid and salts thereof, 5,10-methylene-(6R)-tetrahydrofolic acid and salts thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid and salts thereof, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid salts thereof, (6S)-tetrahydrofolic acid and salts thereof, and combinations of the foregoing. 
     
     
         33 . The method of  claim 31 , wherein said composition further comprises arginine. 
     
     
         34 . A method of treating a patient having above normal concentration of plasma phenylalanine comprising administering to said patient a stabilized BH4 composition in an amount effective to produce a decrease in the plasma phenylalanine concentration of said patient. 
     
     
         35 . The method of  claim 34 , wherein said stabilized BH4 composition is stable at room temperature for more than 8 hours. 
     
     
         36 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration greater than 180 μM prior to administration of said BH4. 
     
     
         37 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration of between 180 μM and 360 μM. 
     
     
         38 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration of between 200 μM and 600 μM. 
     
     
         39 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration of between 600 μM and 1200 μM. 
     
     
         40 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration of between 600 μM and 1200 μM. 
     
     
         41 . The method of  claim 34 , wherein said patient has a plasma phenylalanine concentration greater than 1200 μM. 
     
     
         42 . The method of  claim 34 , wherein said patient is an infant. 
     
     
         43 . The method of  claim 42 , wherein said infant has a plasma phenylalanine concentration greater than 1200 μM. 
     
     
         44 . The method of  claim 34 , wherein said patient is pregnant. 
     
     
         45 . The method of  claim 44 , wherein said patient has a plasma phenylalanine concentration of between about 200 μM to about 600 μM. 
     
     
         46 . The method of  claim 44 , wherein said patient has a plasma phenylalanine concentration greater than 1200 μM. 
     
     
         47 . The method of  claim 34 , wherein said patient is a female of child-bearing age that is contemplating pregnancy. 
     
     
         48 . The method of  claim 47 , wherein said patient has a plasma phenylalanine concentration of between about 200 μM to about 600 μM. 
     
     
         49 . The method of  claim 47 , wherein said patient has a plasma phenylalanine concentration greater than 1200 μM, and said method further comprising administering a protein-restricted diet to said patient. 
     
     
         50 . A method of treating a patient having phenylketonuria, comprising administering to said patient a stabilized BH4 composition in an amount effective to produce a decrease in the plasma phenylalanine concentration of said patient wherein said patient has been diagnosed as unresponsive to a BH4 loading test. 
     
     
         51 . The method of  claim 50 , said method comprising administering between about 10 mg BH4/kg body weight to about 200 mg BH4/kg body weight. 
     
     
         52 . The method of  claim 50 , wherein said BH4 is administered in orally, subcutaneously, sublingually, parenterally, per rectum, per and nares. 
     
     
         53 . The method of  claim 50 , wherein said BH4 is administered daily. 
     
     
         54 . The method of  claim 50 , wherein said BH4 is administered on every alternative day. 
     
     
         55 . The methods of  claim 50 , wherein said BH4 is administered weekly. 
     
     
         56 . The method of  claim 50 , wherein said BH4 is administered in combination with a protein-restricted diet. 
     
     
         57 . The method of  claim 50 , wherein said BH4 is administered as part of a component of a therapeutic protein formulation. 
     
     
         58 . The method of  claim 56 , wherein said protein-restricted diet comprises a normal diet of low-protein containing foodstuff. 
     
     
         59 . The method of  claim 56 , wherein said protein-restricted diet comprises a phenylalanine-free protein diet. 
     
     
         60 . The methods of  claim 56 , wherein said protein-restricted diet is supplemented with non-phenylalanine containing protein supplements. 
     
     
         61 . The method of  claim 60 , wherein said non-phenylalanine containing protein supplements comprise tyrosine. 
     
     
         62 . A method of treating an infant having phenylketonuria, comprising administering a stabilized BH4 composition to said patient in an amount effective to produce a decrease in the plasma phenylalanine concentration of said infant wherein said infant is between 0 and 3 years of age and said infant has a plasma phenylalanine concentration of between about 360 μM to about 4800 μM. 
     
     
         63 . The method of  claim 62 , wherein prior to said administering of BH4 said infant has a phenylalanine concentration of about 1200 μM and said administering of BH4 decreases said plasma phenylalanine concentration to about 1000 μM. 
     
     
         64 . The method of  claim 63 , wherein prior to said administering of BH4 said infant has a phenylalanine concentration of about 800 μM and said administering of BH4 decreases said plasma phenylalanine concentration to about 600 μM. 
     
     
         65 . The method of  claim 63 , wherein prior to said administering of BH4 said infant has a phenylalanine concentration of about 400 μM and said administering of BH4 decreases said plasma phenylalanine concentration to about 300 μM. 
     
     
         66 . The method of  claim 63 , wherein said administering of BH4 decreases said plasma phenylalanine concentration 360±15 μM. 
     
     
         67 . The method of any of  claims 34  to  66 , further comprising administering a folate. 
     
     
         68 . The method of  claim 67 , wherein said folate comprises a tetrahydrofolate selected from the group consisting of tetrahydrofolate is 5-formyl-(6S)-tetrahydrofolic acid and salts thereof, 5-methyl-(6S)-tetrahydrofolic acid and salts thereof, 5,10-methylene-(6R)-tetrahydrofolic acid and salts thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid and salts thereof, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid salts thereof, (6S)-tetrahydrofolic acid and salts thereof, and combinations of the foregoing. 
     
     
         69 . The method of  claim 68 , further comprising administering arginine. 
     
     
         70 . A composition comprising a stabilized, crystallize form of BH4 that is stable at room temperature for more than 8 hours and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         71 . The composition of  claim 70 , wherein said composition further comprises a medical protein supplement. 
     
     
         72 . The composition of  claim 70 , wherein said BH4 composition is part of an infant formula. 
     
     
         73 . The composition of  claim 71 , wherein said protein supplement is phenylalanine free. 
     
     
         74 . The composition of  claim 73 , wherein said protein supplement is fortified with L-tyrosine, L-glutamine, L-carnitine at a concentration of 20 mg/100 g supplement, L-taurine at a concentration of 40 mg/100 g supplement and selenium. 
     
     
         75 . The composition of  claim 74 , wherein said protein supplement further comprises the recommended daily dose of calcium and phosphorus. 
     
     
         76 . The composition of  claim 74 , wherein said protein supplement further comprises the recommended daily dose of one or more amino acids selected from the group consisting of L-leucine, L-proline, L-lysine acetate, L-valine, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-tryptophan, L-serine, L-threonine, L-histidine, L-methionine, L-glutamic acid, and L-aspartic acid. 
     
     
         77 . The composition of  claim 74 , wherein said protein supplement is further fortified with the recommended daily dosage of vitamins A, D and E. 
     
     
         78 . The composition of  claim 73 , wherein said protein supplement comprises a fat content that provides at least 40% of the energy of said supplement. 
     
     
         79 . The composition of  claim 73 , wherein said composition is in the form of a powder. 
     
     
         80 . The composition of  claim 71 , wherein said composition is in the form of a protein bar. 
     
     
         81 . The composition of  claim 70 , further comprises a folate. 
     
     
         82 . The composition of  claim 81 , wherein said folate comprises a tetrahydrofolate selected from the group consisting of tetrahydrofolate is 5-formyl-(6S)-tetrahydrofolic acid and salts thereof, 5-methyl-(6S)-tetrahydrofolic acid and salts thereof, 5,10-methylene-(6R)-tetrahydrofolic acid and salts thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid and salts thereof, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid salts thereof, (6S)-tetrahydrofolic acid and salts thereof, and combinations of the foregoing. 
     
     
         83 . The composition of  claim 82 , further comprising arginine.