Deoxyribonucleoside monophospate bypass therapy for mitochondrial dna depletion syndrome

Abstract

The invention relates generally to a pharmacological therapy for a human genetic diseases, specifically mitochondrial DNA depletion syndromes, and more specifically, thymidine kinase 2 (TK2) deficiency. The pharmacological therapy involves the administration of at least one deoxyribonucleoside monophosphate, or mixtures thereof. For the treatment of TK2 deficiency, the pharmacological therapy involves the administration of either deoxythymidine monophosphate (dTMP) or deoxycytidine monophosphate (dCMP), or mixtures thereof. This molecular bypass approach is applicable to other disorders of unbalanced nucleotide pools, especially those found in mitochondrial DNA depletion syndrome.

1 . A method of treating mitochondrial DNA depletion syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one deoxyribonucleoside monophosphate. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the mitochondrial DNA depletion syndrome is chosen from the group consisting of deoxyguanosine kinase (dGK) deficiency, thymidine phosphorylase (TP) deficiency, and mutations in the RRM2B gene. 
     
     
         4 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         5 . The method of  claim 1 , wherein the subject is a human. 
     
     
         6 . The method of  claim 1 , wherein the composition comprises two or more deoxyribonucleoside monophosphates. 
     
     
         7 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day. 
     
     
         14 . The method of  claim 11 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of each deoxyribonucleoside monophosphate in the composition. 
     
     
         15 . The method of  claim 11 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of the total deoxyribonucleoside monophosphates in the composition. 
     
     
         16 . The method of  claim 12 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day of each deoxyribonucleoside monophosphate in the composition. 
     
     
         17 . The method of  claim 12 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day of the total deoxyribonucleoside monophosphates in the composition. 
     
     
         18 . The method of  claim 13 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day of each deoxyribonucleoside monophosphate in the composition. 
     
     
         19 . The method of  claim 13 , wherein the composition comprises more than one deoxyribonucleoside monophosphate and the therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day of the total deoxyribonucleoside monophosphates in the composition. 
     
     
         20 . The method of  claim 1 , wherein the composition is administered once daily, twice daily, three times daily, four times daily, five times daily or six times daily. 
     
     
         21 . The method of  claim 1 , wherein the composition administered orally, intrathecally, enterally, or intravenously. 
     
     
         22 . The method of  claim 21 , wherein the composition is administered orally and comprises deoxyribonucleoside monophosphates mixed with cow's milk, human breast milk, infant formula or water. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the therapeutically effective amount of the composition administered to the subject is increased over time. 
     
     
         28 . The method of  claim 27 , wherein a first therapeutically effective amount of the composition administered to the subject is about 100 mg/kg/day of composition, and wherein the therapeutically effective amount of the composition is increased over time to 200 mg/kg/day, to 400 mg/kg/day, to 800 mg/kg/day, up to 1000 mg/kg/day. 
     
     
         29 - 32 . (canceled) 
     
     
         33 . The method of  claim 2 , wherein the mitochondrial DNA depletion syndrome is deoxyguanosine kinase (dGK) deficiency and the deoxyribonucleoside monophosphate is chosen from the group consisting of deoxyadenosine monophosphate (dAMP), deoxyguanosine monophosphate (dGMP), and mixtures thereof and mixtures thereof. 
     
     
         34 . The method of  claim 2 , wherein the mitochondrial DNA depletion syndrome is thymidine phosphorylase (TP) deficiency and the deoxyribonucleoside monophosphate is thymidine 5′-monophosphate (TMP).