Claims for Patent: 10,471,087

Summary for Patent: 10,471,087

Title:	Deoxynucleoside therapy for diseases caused by unbalanced nucleotide pools including mitochondrial DNA depletion syndromes
Abstract:	The invention relates generally to a pharmacological therapy for human genetic diseases, specifically those characterized by unbalance nucleotide pools, more specifically mitochondrial DNA depletion syndromes, and more specifically, thymidine kinase 2 (TK2) deficiency. The pharmacological therapy involves the administration of at least one deoxynucleoside, or mixtures thereof. For the treatment of TK2 deficiency, the pharmacological therapy involves the administration of either deoxythymidine (dT) or deoxycytidine (dC), or mixtures thereof. This administration of deoxynucleosides is applicable to other disorders of unbalanced nucleotide pools, especially those found in mitochondrial DNA depletion syndrome.
Inventor(s):	Michio Hirano, Caterina Garone, Ramon Marti
Assignee:	Columbia University in the City of New York
Application Number:	US15/736,092
Patent Claims:	1. A method of treating thymidine kinase 2 (TK2) deficiency in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a mixture of deoxycytidine (dC) and deoxythymidine (dT), wherein the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of each deoxynucleoside in the composition. 2. The method of claim 1, wherein the therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day of each deoxynucleoside in the composition. 3. A method of treating thymidine kinase 2 (TK2) deficiency in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a mixture of deoxycytidine (dC) and deoxythymidine (dT), wherein the therapeutically effective amount is between about 100 mg/kg/day and about 1000 mg/kg/day of the total deoxynucleoside in the composition. 4. 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. 5. The method of claim 1, wherein the composition administered orally, intrathecally, enterally, or intravenously. 6. The method of claim 5, wherein the composition is administered orally and further comprises cow's milk, human breast milk, infant formula or water. 7. The method of claim 1, further comprising administering to the subject an additional agent chosen from the group consisting of an inhibitor of thymidine phosphorylase and an inhibitor of cytidine deaminase. 8. The method of claim 1, wherein the therapeutically effective amount of the composition administered to the subject is increased over time. 9. The method of claim 8, wherein a first therapeutically effective amount of the composition administered to the subject is about 100 mg/kg/day of composition of each deoxynucleoside in the 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 of each deoxynucleoside in the composition. 10. The method of claim 1, 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. 11. The method of claim 10, wherein if the determination of no improvement is made in step (d), the therapeutically effective amount of the composition is increased. 12. The method of claim 1, further comprising monitoring the subject for an adverse effect after the administration of the composition, wherein if an adverse effect is observed, the therapeutically effective amount of the composition is decreased. 13. The method of claim 12, further comprising monitoring the subject for the observed adverse effect after the therapeutically effective amount of the composition is decreased, wherein if the adverse effect is no longer observed, the therapeutically effective amount of the composition is increased. 14. The method of claim 1, wherein the therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day of each deoxynucleoside in the composition. 15. The method of claim 1, wherein the therapeutically effective amount is between about 100 mg/kg/day and about 400 mg/kg/day of each deoxynucleoside in the composition. 16. The method of claim 3, wherein the he therapeutically effective amount is between about 200 mg/kg/day and about 800 mg/kg/day of the total deoxynucleoside in the composition. 17. The method of claim 3, wherein the he therapeutically effective amount is between about 250 mg/kg/day and about 400 mg/kg/day of the total deoxynucleoside in the composition. 18. The method of claim 1, wherein the ratio of deoxycytidine (dC) and deoxythymidine (dT) is 50/50, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5. 19. The method of claim 1, wherein the ratio of deoxycytidine (dC) and deoxythymidine (dT) is 50/50. 20. The method of claim 3, wherein the therapeutically effective amount of the composition administered to the subject is increased over time. 21. The method of claim 20, 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. 22. The method of claim 3, wherein the composition is administered once daily, twice daily, three times daily, four times daily, five times daily or six times daily. 23. The method of claim 3, wherein the composition administered orally, intrathecally, enterally, or intravenously. 24. The method of claim 23, wherein the composition is administered orally and further comprises cow's milk, human breast milk, infant formula or water. 25. The method of claim 3, further comprising administering to the subject an additional agent chosen from the group consisting of an inhibitor of thymidine phosphorylase and an inhibitor of cytidine deaminase. 26. The method of claim 3, 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. 27. The method of claim 26, wherein if the determination of no improvement is made in step (d), the therapeutically effective amount of the composition is increased. 28. The method of claim 3, further comprising monitoring the subject for an adverse effect after the administration of the composition, wherein if an adverse effect is observed, the therapeutically effective amount of the composition is decreased. 29. The method of claim 28, further comprising monitoring the subject for the observed adverse effect after the therapeutically effective amount of the composition is decreased, wherein if the adverse effect is no longer observed, the therapeutically effective amount of the composition is increased. 30. The method of claim 3, wherein the ratio of deoxycytidine (dC) and deoxythymidine (dT) is 50/50, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5. 31. The method of claim 3, wherein the ratio of deoxycytidine (dC) and deoxythymidine (dT) is 50/50.