Deoxyribonucleoside monophospate bypass therapy for mitochondrial dna depletion syndrome

Patent metadata

Field	Value
Publication number	US-2016279159-A1
Application number	US-201615082207-A
Country	US
Kind code	A1
Filing date	Mar 28, 2016
Priority date	Mar 26, 2015
Publication date	Sep 29, 2016
Grant date	—

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.

First claim

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 . The method of claim 1 , wherein the mitochondrial DNA depletion syndrome is thymidine kinase 2 (TK2) deficiency.

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 . The method of claim 1 , wherein the deoxyribonucleoside monophosphate is a deoxypyrimidine monophosphate.

8 . The method of claim 7 , wherein the deoxypyrimidine monophosphate is chosen from the group consisting of deoxycytidine monophosphate (dCMP), deoxythymidine monophosphate (dTMP), and mixtures thereof.

9 . The method of claim 1 , wherein the deoxyribonucleoside monophosphate is a deoxypurine monophosphate.

10 . The method of claim 9 , wherein the deoxypurine monophosphate is chosen from the group consisting of deoxyadenosine monophosphate (dAMP), deoxyguanosine monophosphate (dGMP), and mixtures thereof.

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 . The method of claim 1 , further comprising administering to the subject an inhibitor of thymidine phosphorylase.

24 . The method of claim 23 , wherein the inhibitor of thymidine phosphorylase is tipiracil.

25 . The method of claim 1 , further comprising administering to the subject an inhibitor of cytidine deaminase.

26 . The method of claim 25 , wherein the inhibitor of cytidine deaminase is tetrahydrouridine [THU].

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 . A method for the treatment of TK deficiency in a subject comprising:
a. obtaining a sample from the subject, said sample comprising nucleic acid; b. performing sequence analysis of the TK2 gene in the nucleic acid of the subject; c. determining the subject has TK2 deficiency when a homozygous mutation or compound heterozygous mutations in the TK2 gene is detected; and d. administering a therapeutically effective amount of a composition comprising deoxycytidine monophosphate (dCMP), deoxythymidine monophosphate (dTMP), and mixtures thereof to the subject.

30 . The method of claim 29 , further comprising:
a. detecting the level of creatine kinase concentration in a sample from the subject; b. performing a biopsy on skeletal muscle of the subject; c. measuring mitochondrial DNA count in skeletal muscle of the subject; and d. further determining and/or confirming the subject has TK2 deficiency if one or more of the following is detected: the levels of creatine kinase concentration are increased or elevated compared to healthy controls; the skeletal muscle of the subject comprises prominent variance in fiber size, variable sarcoplasmic vacuoles, variable increased connective tissue, ragged red fibers, and cytochrome c oxidase (COX) deficient fibers: and mitochondrial DNA levels are decreased compared to healthy controls.

31 . The method of claim 2 , further comprising monitoring the subject after the administration of the composition, comprising:
a. observing muscle strength and control; b. observing differences in height and weight; c. observing mobility; and d. determining an improvement in condition of the subject if any of observations (a)-(c) are increased after administration of the composition, and determining no improvement if any of observations (a)-(c) are the same or decreased after administration of the composition.

32 . The method of claim 31 , wherein if the determination of no improvement is made in step (d), the therapeutically effective amount of the composition is increased.

Assignees

• Univ Columbia

Inventors

• Hirano Michio
• Garone Caterina

Classifications

• A61K31/708

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61K31/7072 Primary

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title